Georgia Cancer Center 2016 Scientific Report

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2016 Scientific Report

Georgia Cancer Center 2016 Scientific Report Table of Contents Introduction……...……...……...……...……...……...……...……...……..

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Cancer immunology, Inflammation, and Tolerance (CIT) Program ……... 8 Molecular Oncology and Biomarkers (MOB) Program ……...……...…..… 21 Tumor Signaling and Angiogenesis (TSA) Program ……...……...……..….. 40 Cancer Prevention and Control (CPC) Program ……...……...……….…… 52 Community Outreach...……...……...……...……...……...……………..…. 62 Education Program……...……...……...……...……...……...…………..… 64 Cancer Center Shared Resources…………………………………………….……………..

Bioinformatics……...……...……...……...……...……...….………

Biostatistics ………………………………………….……...……...….…...…..

Flow Cytometry Core……...……...……...………………….…….

Small Animal Imaging ……………………….…...……...……...…..…….

Biorepository……...………………………….…...……...……..…

Integrated Genomics……...……...…..……...…..……...…..…...…

Proteomics and Metabolomics……...……...……...……...…….....

66 67 68 69 70 71 72 73

Translational and Clinical Research …...……...……...………..………….. 74 2016 Georgia Cancer Center Publications……...……...……...……...…… 79

2016 Scientific Report

About the Georgia Cancer Center The Georgia Cancer Center at Augusta University (AU), formerly GRU Cancer Center at Georgia Regents University, is a multi-disciplinary academic cancer center with a mission to reduce the burden of cancer in Georgia and across the globe through superior care, innovation and education. Its patientcentered approach includes first-in-the-nation treatment protocols, an experimental therapeutics program, and specialized clinics for state-of-the-art drug and immunotherapy clinical trials. In 2016, in conjunction with the rebranding of AU, the GRU Cancer Center became the Georgia Cancer Center, a name reflecting its role as the State of Georgia’s official cancer center.

With strong state support, AU has invested substantially in developing the Cancer Center. In 2006, a $54 million, 151,000 square-foot research building was erected to house Cancer Center scientific laboratories, shared facilities, and administration. In 2010, a $31 million, 64,000 square-foot adult cancer clinical facility opened, providing comprehensive outpatient oncology services and housing a dedicated clinical trials unit. In early 2012, the two units merged to become what we now know as the Georgia Cancer Center, with members recruited from colleges, departments and institutes at AU and from the very finest cancer centers across the country.

Today the growth continues. The Cancer Center is currently under construction toward a 78,000 square-foot expansion project that will not only add much needed research and clinical space, but will also quite literally bridge the gap between the Cancer Center’s clinical and research missions. This $62.5 million dollar project will include a five-story addition to the existing research building and a three-story ‘bridge’ building connecting the research and clinical facilities, designed to foster collaboration and communication. The project is expected to be completed in early 2018.

About Augusta University Augusta University (AU) generates national and global impact through groundbreaking research, patient-centered clinical expertise and forward-thinking educational programs from three campuses in the beautiful Southern city of Augusta, Georgia, and satellite locations across the state. Nearly 9,000 students choose AU for advanced health sciences and liberal arts education. Home to the state’s only public academic medical center, AU’s world-class clinicians are bringing the medicine of tomorrow to patient care today.

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Georgia Cancer Center Senior Leadership Nationally and internationally recognized leaders in clinical care and scientific research have been recruited to serve at the Georgia Cancer Center in the following capacities:

Samir N. Khleif, MD Director, Georgia Cancer Center Director, Georgia Cancer Center Service Line

Sharad Ghamande, MD Associate Director Clinical Affairs

Michael Benedict, PharmD Associate Director Administration

Nita J. Maihle, PhD Associate Director Education

John K. Cowell, PhD, DSc, FRCPath Associate Director Basic Science

David H. Munn, MD Senior Advisor to the Director

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Georgia Cancer Center 2016 Scientific Report Presented here is the Annual Scientific Report of the Georgia Cancer Center at Augusta University (AU), formerly Georgia Regents University, in Augusta, Georgia. The following pages describe the 2016 research achievements of Cancer Center members within the Cancer immunology, Inflammation, and Tolerance (CIT), Molecular Oncology and Biomarkers (MOB), and Tumor Signaling and Angiogenesis (TSA) basic science programs, as well as the newly established Cancer Prevention and Control (CPC) Program and other important initiatives.

The Cancer Center’s Translational Oncology initiative is progressing with the establishment of infrastructure required to support Phase I/II clinical trials, including investigator-initiated trials that develop from within Cancer Center research laboratories. Cancer Center clinical trials that opened to accrual in 2016 have been added to this report; see “Translational and Clinical Research.”

Under the leadership of Dr. Samir Khleif, the Georgia Cancer Center has undergone unprecedented expansion in the number of research and clinical faculty with the recruitment of more than twenty new faculty. The plan is to further increase this number to build the critical mass needed to achieve NCI designation through the National Cancer Institute’s Cancer Center Support Grant program. With this goal in mind, prioritized development of shared research resources provides access to state-ofthe-art technologies to all Cancer Center members. Details of these shared facilities and the services they offer are included in this report, as are the many publications generated by Cancer Center members.

An additional asset of the Georgia Cancer Center is the integration of its research program with its education and community outreach programs. Over the past year, new educational components have been developed to secure the best training for the next generation of physicians and scientists, to provide optimized idea exchange among established physicians and scientists, and to ensure that current clinical professionals integrate the best, most up-to-date practices in medicine. Community outreach continues to provide cancer information and awareness materials to community and university partners, covering such areas as tobacco cessation, skin cancer prevention, and screening for breast, colorectal, and lung cancers. Cooperation among the research, education, and community outreach programs ensures that Georgia Cancer Center patients benefit from the most recent research discoveries from around the world.

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Cancer immunology, Inflammation, & Tolerance

Cancer immunology, Inflammation, & Tolerance

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OVERVIEW

The field of cancer immunotherapy continues to explode due to the approval of several novel immune modulators that have shown remarkable therapeutic effects against several tumor types. The goals of the Cancer immunology, Inflammation, and Tolerance (CIT) Program are: A) studying how the immune system can recognize alterations caused by malignant transformation; B) examining those immune inflammatory processes that cause cancer, and C) developing immune-based strategies to prevent and treat cancer. This will be accomplished by: understanding how inflammation contributes to malignant transformation; improving immune responses to tumor antigens through the development of therapeutic vaccines or adoptive cell therapies; and blocking immune suppressive activities that limit the effectiveness of anti-tumor immune responses. A major impetus of all CIT members is to translate knowledge acquired from basic research into the clinical setting. To achieve this goal, CIT-specific areas of interest include:  Elucidating how chronic inflammation creates tolerance to protect tumors and healthy tissues from immune-mediated injury

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Understanding how the interplay between dietary fiber and gut microbiota suppresses chronic inflammation and carcinogenesis

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Discovery research using models of chronic inflammatory diseases to elucidate how immune responses are regulated to create tolerance (unresponsiveness) in tumor microenvironments that inhibit natural and vaccine-induced anti-tumor immunity and to identify novel targets for therapeutic intervention

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Development and characterization of molecular and immunological strategies for manipulating innate and adaptive immune responses to malignancy

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Translating new discoveries into clinical settings in collaboration with experimental oncologists in the Georgia Cancer Center, Augusta University collaborators, and corporate partners

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Evaluating the efficacy of immunotherapy and conventional therapies by developing a system to monitor immune response in conjunction with clinical outcomes

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Manipulating immune tolerance and immune checkpoint mechanisms for clinical benefit

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Studying the interactions between tumor cells and surrounding stroma, which affect disease progression and metastases and impede immunotherapy

Developing more efficient cancer vaccines Elucidating novel targets to manipulate immune responses to treat cancer Understanding how commensal microbiota or commensal dysbiosis influences innate and adaptive immune responses to natural and vaccine-induced anti-tumor immunity

CIT Program Member

Laboratory Focus

Jennifer W. Bradford, PhD

How cancer cells and tumor-associated macrophages communicate via the nuclear factor-kappaB (NF-ÎşB) pathway to promote aggressive cancer properties

Esteban Celis, MD, PhD

Development of T cell-based immunotherapy for cancer

Yan Cui, PhD

Tumor-host immune cell interaction that dictates the immunological landscape of the tumor microenvironment (TME) and how to alter the immunosuppressive TME to enhance anti-tumor immunity

Yukai He, MD, PhD

Developing effective cancer vaccines and immunotherapy approaches for primary hepatocellular carcinoma (HCC)

Theodore S. Johnson, MD, PhD

The contribution of indoleamine 2,3-dioxygenase (IDO) to immunological tumor tolerance and related clinical trials

Samir N. Khleif, MD

Enhancing the anti-tumor immune response by optimizing the activation of tumor-specific cytotoxic T lymphocytes (CD8+ effector T cells) while subsiding the immune suppressive mechanisms within the tumor microenvironment, mostly through minimizing the activity of regulatory T lymphocytes (Tregs)

Pandelakis Koni, PhD

The mechanisms whereby the immune system is regulated and how this knowledge might be translated into new therapeutics for the treatment of autoimmune diseases and cancer

Zoya B. Kurago, DDS, PhD

The functions of the mucosal defenses of the upper aerodigestive tract in health and disease, including infectious disorders and malignant neoplasia

Kebin Liu, PhD

To develop molecular target-based therapy to enhance the efficacy of T cell cancer immunotherapy

Santhakumar Manicassamy, PhD

To understand how commensal flora shapes innate and adaptive immune responses in the intestine and periphery

David H. Munn, MD

The molecular mechanisms of immune suppression and tolerance in the tumor microenvironment

Paulo C. Rodriguez, PhD

To develop innovative strategies that restore protective immunity in cancer, leading to long-lasting anti-tumor effector T cell responses

Nagendra Singh, PhD

To study how interaction between dietary fiber and gut microbiota influences intestinal inflammation and carcinogenesis

Gang Zhou, PhD

How to combine standard-of-care chemotherapy and CD4+ T cellbased immunotherapy in a synergistic manner to treat cancer

Cancer immunology, Inflammation, & Tolerance

CIT Program Members

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Jennifer Bradford, PhD

Cancer immunology, Inflammation, & Tolerance

Assistant Professor

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The Bradford laboratory focuses on how cancer cells and tumor-associated macrophages communicate via the nuclear factor-kappaB (NF-κB) pathway to promote aggressive cancer properties. NF-κB is a family of five transcription factors (RelA/p65, RelB, p50, p52, c-Rel) that form different dimers to regulate target gene expression in diverse biological functions, including normal immune function, synaptic plasticity, and even memory. Aberrant NF-κB activity is associated with autoimmune diseases, and importantly, cancer. The Bradford laboratory has developed an animal model that lacks p65 protein in cells of the myeloid lineage. From these animals, they are able to harvest and utilize bone marrow-derived macrophages that lack p65 protein, and therefore, have dysfunctional NF-κB signaling. Cell culture and other in vitro experiments are possible with these cells to determine the role of NF-κB in the relationship between cancer cells and tumor-associated macrophages.

The laboratory’s research efforts in the area of NF-κB signaling in glioma continued this past year due to collaboration with Dr. Ali Arbab’s laboratory (Georgia Cancer Center) and funding provided by the Georgia Cancer Center/Summerville Collaborative Research Award. The group has found that stimulation of glioblastoma (GBM) cell lines with bone marrow-derived macrophage-conditioned media from control cells, but not from cells lacking p65, elevates GBM NF-κB signaling and increases stem cell properties.

The collaboration is investigating how the lack of NF-κB signaling in cells of the myeloid lineage can alter syngeneic GBM growth via MRI in animal models. Recent data suggest that NF-κB signaling is important in GBM growth and macrophage polarity, which could initiate new treatment options for patients with this very aggressive cancer.

Ongoing work includes examining stem cell properties using GBM cell lines and conditioned media from control macrophages or macrophages lacking p65, and examining brain microglia in the laboratory’s animal model.

Esteban Celis, MD, PhD Co-Leader, CIT Program Georgia Research Alliance, Professor The main focus of the Celis laboratory is the development of T cell-based immunotherapy for cancer.

The laboratory has reported a strategy to improve the efficacy of therapeutic peptide vaccines for various tumor types in mice by mimicking acute viral infections (Cancer Immunol. Immunother. 2016, doi:10.1007/s00262-016-1834-5). This approach is based on the systemic administration of synthetic peptides together with synthetic immune adjuvants that resemble viral components. In another study, a strategy to generate large numbers of CD4 T cells after peptide vaccination in mice was described (Cancer Immunol Res. 2017 5(1):72-83). In collaboration with a group of Japanese researchers at Asahikawa Medical University, it was shown that the human leukocyte antigen G can serve as a tumor antigen for T cell-based immunotherapy (Oncoimmunology. 2016, 30;5(6):e1169356. doi: 10.1080/2162402X.2016.1169356). In another collaborative study, the Celis group working with the Rodriguez laboratory (Georgia Cancer Center, Augusta University) recently reported that T cells conditioned with myeloid-derived suppressor cells (MDSCs) increased anti-tumor function in mice after adoptive T cell transfers (Oncotarget. 2016, 7(14):17565-78). Based on previous preclinical studies in collaboration with Drs. S. Khleif and J. Janik (Georgia Cancer Center, Augusta University), an investigatorinitiated phase I/II clinical study will soon start at the Georgia Cancer Center. This study is sponsored by Merck and evaluates the use of a checkpoint inhibitor (PD-1) blocker (pembrolizumab) and an immune stimulator (poly-ICLC) in colon carcinoma patients (NCT02834052). Dr. Celis’s current efforts are being devoted to finding strategies to enhance T cell infiltration into solid tumors, which is one of the main barriers to developing effective cancer immunotherapy.

Cancer immunology, Inflammation, & Tolerance

Cecil F. Whitaker Jr MD Eminent Scholar in Cancer Immunology

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Cancer immunology, Inflammation, & Tolerance

Yan Cui, PhD Professor

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The Cui laboratory studies tumor-host immune cell interactions that dictate the immunological landscape of the tumor microenvironment (TME) and how to alter the immunosuppressive TME to enhance anti-tumor immunity.

One area of research focus centers on the cellular and molecular characteristics of fibroblastic reticular cells (FRCs) of the lymphoid tissues and cancer associated fibroblasts (CAFs) and how these stromal cells enforce immunosuppression to T cells in the lymphoid tissues and TME. We recently discovered that during homeostasis these stromal cells express a high level of cyclooxygenase-2 (COX-2), which suppresses T cell activation and function via PGE2 production. It has been shown previously that the hyperactive COX-2/PGE2 axis represents one of the detrimental mechanisms that some tumors employ for immune suppression and escape. Thus, it is intriguing and important to understand how these stromal cells maintain highly elevated COX-2/PGE2 activity. We are currently in the process of elucidating the cellular and molecular pathways involved in tissue-specific activation of the COX-2/PGE2 pathway in lymphoid tissues and in the TME and its immunological impacts on immune tolerance.

The other area of our research focus is targeting the tumor suppressor p53 pathway in the TME as an immunotherapy approach to alter host immune function and tumor milieu. Tumor suppressor p53 dysfunction via mutation is a vital mechanism of tumor escape from apoptosis and senescence. Previous studies in our laboratory and those of others suggest that p53 dysfunction also fuels inflammation and supports tumor immune evasion, thereby serving as an immunological driver of tumorigenesis. Therefore, targeting p53 in the TME represents an important immunological target for reversing immunosuppression and enhancing anti-tumor immunity (Int J Mol Sci. 2016,17(11). PMID:27869779). Using a pharmacological p53 activator, nutlin-3a, we show that local p53 activation in the TME elicits strong antitumor immunity, leading to improved tumor control and even tumor elimination (Cancer Res, under revision). Unlike conventional nutlin-3a-based tumoricidal therapies, which rely on effective p53 targeting in each tumor cell and is often associated with systemic toxicity, this immune-based strategy requires only limited, local p53 activation to alter the immune landscape of the TME and subsequently amplify the anti-tumor immune response to systemic immunity. The study demonstrates that targeting the p53 pathway in the TME can be exploited to reverse immunosuppression and augment therapeutic benefits beyond the sole tumoricidal effects to harness tumor-specific, durable, and systemic anti-tumor immunity with minimal toxicity.

The research focus of Dr. He’s laboratory has been on developing effective cancer vaccines and immunotherapy approaches for primary hepatocellular carcinoma (HCC), one of the fastest growing malignancies in the United States with a high mortality rate due to the lack of effective therapies.

Regarding HCC cancer vaccine development, Dr. He’s research group has generated a proof-of-principle mouse model showing that antigen engineering by epitope optimization is a valid approach for creating highly immunogenic cancer vaccines with a strong anti-tumor effect. This work in the context of HCC cancer vaccine research by targeting alpha fetoprotein antigen was summarized recently (He Y, Wu S. 2016. Chapter 20: Engineering alpha-fetoprotein to develop vaccines and T cell immunotherapies for hepatocellular carcinoma: From preclinical studies to future perspectives. In: Lakhi N, Moretti M, editors.

Alpha Fetoprotein, Function and Clinical Applications. New York (NY): Nova Publishers. p. 375-91). Currently, in collaboration with Dr. Bjoern Peters (La Jolla Institute for Allergy and Immunology), Dr. He is designing HCC vaccines by epitope optimization that can activate both CD8 and CD4 T cells, aiming at achieving maximal activation of liver cancer-specific immune responses. In addition, this important finding is being translated into developing human HCC cancer vaccines that can be used to activate human T cells to prevent and to treat human HCC. The He laboratory is also interested in understanding the basic mechanisms of immune activation and deciphering the parameters that can affect the anti-tumor efficacy of vaccine-activated immune effector cells. The research led to the discovery of some very interesting findings that may shed light on explaining the phenomena of why some high-level antigen-specific T cells do not correlate with an anti-tumor effect. It has been shown that the induction of stem-like memory T cells by cancer vaccines is associated with T cell receptor (TCR) down-regulation and correlates with a strong anti-tumor effect. The knowledge gained from this study will help design more effective vaccines that can better elicit a potent anti-tumor effect.

Additionally, Dr. He’s laboratory has a continued interest in understanding the immune suppressive tumor microenvironment and in modulating the inflammation status of the tumor microenvironment to improve the anti-tumor effect of liver cancer vaccines. A collaboration with Dr. Xue-Feng Bai (Ohio State University) showed that Ebi3 gene-mediated IL27 production is critical in relieving immune suppression in the tumor microenvironment, and in collaboration with Dr. S. Manicassamy (Georgia Cancer Center), the role of the Wnt signaling pathway in immune suppression of the tumor microenvironment has been demonstrated.

Cancer immunology, Inflammation, & Tolerance

Yukai He, MD, PhD Professor

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Theodore S. Johnson, MD, PhD

Cancer immunology, Inflammation, & Tolerance

Associate Professor

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The Johnson laboratory uses animal models of in vivo solid tumor growth to study the contribution of indoleamine 2,3-dioxygenase (IDO) to immunological tumor tolerance. Normally, IDO functions to limit immune responses against innocuous exposures, such as commensal bacteria and normal dying (apoptotic) cells. However, IDO is also widely expressed in human tumors and tumor-draining lymph nodes, where it can suppress desirable anti-cancer immune responses (“Overcoming Immunosuppression.” In: Gray J and Marabelle A, ed. Immunotherapy for Paediatric Malignancies. New York: Springer (in press); “Chemo-immunotherapy: impact of indoleamine 2,3-dioxygenase in defining immunogenic versus tolerogenic cell death in the tumor microenvironment”. In Kalinski P, ed. The Microenvironment in Cancer Progression and Cancer Therapy. New York: Springer, (2016)).

Recently, the Johnson laboratory also made the novel discovery that when IDO is blocked, (i) conventional chemotherapy can drive intense intra-tumoral vasculitis, and (ii) conventional chemotherapy with radiation can drive complement-mediated tumor rejection. Thus, blocking IDO during chemo-radiation therapy elicits synergistic effects on survival and changes the nature of the tumor response in tumor models. The central hypothesis is that the interaction between IDO and complement functions as a previously unrecognized regulator of intra-tumoral inflammation following chemo-radiation therapy, and that this pathway critically regulates the ability of chemo-radiation to cause tumor destruction. Ongoing projects study the role of IDO and complement in tumor immunology, testing the hypothesis that IDO acts as a crucial modulator of therapy-induced inflammation in solid tumors by inhibiting production of pro-inflammatory cytokines and suppressing activation of complement.

Dr. Johnson’s team has successfully translated their findings to clinical trials using indoximod to block IDO during standard chemotherapy and/or radiation for patients with glioblastoma. Clinical trials developed as a result of their research include: “A phase I/II study of the combination of indoximod and temozolomide for adult patients with temozolomide-refractory primary malignant brain tumors” (PI: Samir Khleif, Georgia Cancer Center; Co-I: Johnson, NCT02052648, open at 17 sites in 13 states for patients 16 years and older with glioblastoma) and “Phase I trial of indoximod in combination with temozolomidebased therapy for children with progressive primary brain tumors” (PI: Johnson, NCT02502708, open at 2 sites in Georgia for children age 3-21 years with relapsed or progressive brain tumors) These clinical trials test the hypothesis that adding IDO blockade to standard temozolomide therapy, or to radiation therapy followed by temozolomide, will be safe and tolerable in adults and children with relapsed brain tumors, and that this combination immuno-chemotherapy will show preliminary evidence of synergistic efficacy.

Kebin Liu, PhD

The research program in the Liu laboratory in 2016 has been devoted to four areas: 1) Genetic and epigenetic regulation of PD-L1 in colon and pancreatic cancer cells and myeloid-derived suppressor cells (MDSCs). It has been shown that PD-L1 expression is regulated by MLL1-mediated H3K4me3 in tumor cells, and that targeting PD-L1 expression can effectively enhance the efficacy of anti-PD-L1 antibody immunotherapy to suppress pancreatic cancer growth (JNCI. 2016, in press). Furthermore it was determined that PD-L1 is abundantly expressed in tumor-induced MDSCs in human colon carcinoma, and its regulatory mechanism has been described (OncoImmunology. 2016, in press). 2) Identification of a subset of colon cancer stem cell-like cells that is responsible for colon cancer 5-FU resistance. 5-FU is the mainstay of therapy for human patients with advanced colorectal cancer. However, almost all patients develop resistance to 5-FU, which accounts for over 90% mortality. Using genome-wide gene expression profiling, the Liu laboratory has identified CD133+CD24lo colon cancer cells as cancer stem cell-like cells that are responsible for colon cancer chemoresistance (Oncotarget. 2016, doi: 10.18632/ oncotarget.12168). 3) NF-κB functions as a molecular link between immune cells and cancer cells in the tumor microenvironment. Low level NF-κB activity is constitutively present in many types of human cancer cells, and NF-κB activation often promotes tumor growth and progression, providing a strong rationale for anticancer strategies that inhibit NF-κB signaling. However, compelling experimental data now show that NF-κB also acts to promote apoptosis in multiple types of cells. The Liu group has determined that NF-κB regulates gene expression in both tumor cells and immune cells in the tumor microenvironment to exert radiation-induced tumor suppression (Oncotarget. 2016, 7:23395-415. doi: 10.18632/oncotarget.8246). 4) Development of ceramide-based targeted therapy to enhance the efficacy of CTL-based cancer immunotherapy. The crucial roles of ceramide in tumor development and cancer cell responses to therapy have led to extensive efforts to target the ceramide metabolism pathways for anticancer therapy. In studies designed to elucidate the molecular mechanism underlying ceramide function in colon cancer cells, five novel ceramide analogs have been developed that exhibit potent sensitization activity to increase the efficacy of tumor-specific CTLs (Sci. Rep. 2016, 6:30816). Overall, the Liu laboratory’s research goal is to develop molecular target-based therapy to enhance the efficacy of T cell cancer immunotherapy.

Cancer immunology, Inflammation, & Tolerance

Associate Professor

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Santhakumar Manicassamy, PhD

Cancer immunology, Inflammation, & Tolerance

Assistant Professor

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The main research focus of Dr. Manicassamy’s laboratory is to understand how commensal flora shapes innate and adaptive immune responses in the intestine and periphery. The compositions of gut microbial communities have profound effects on human health. Alterations in the microbial composition in the intestine have been linked to inflammatory diseases, obesity, and cancer. The Manicassamy laboratory addresses a central problem in immunology: how the immune system launches robust immunity against pathogens, while maintaining tolerance to self-antigens, food antigens, and commensal bacteria. Addressing this problem will shed light on immunological processes that are critical for maintaining homeostasis with the microbiota and how these interactions can become dysfunctional to cause increased risk of inflammatory diseases, infection by microbial pathogens, and cancer. In this context, the laboratory previously showed that activation of the Wnt/beta-catenin pathway in dendritic cells is critical for maintaining intestinal homeostasis and systemic tolerance to self-antigens (Front Immunol, in press). Dietary components regulate microbial composition and immunity in the intestine. Accumulating evidence also suggests that intestinal inflammation is inextricably linked to altered microbial composition and loss of immune homeostasis. Dietary lipids such as saturated and unsaturated long chain fatty acids are widely present in the intestine and are critical for colonic health. They also play an important role in preventing inflammation in the gastrointestinal track. These lipids regulate inflammation by modulating immune cell function by either activating or suppressing specific transcription factors. However, molecular mechanisms by which dietary lipids shape innate and adaptive immune responses to commensal flora and pathogens remain largely unknown. In a recent study, Dr. Manicassamy’s group has shown that the PPARα pathway in innate immune cells orchestrates gut mucosal immunity and commensal homeostasis by regulating the expression of IL-22 and the antimicrobial peptides RegIIIβ, RegIIIγ, and calprotectin (J Immunol. 2016, 195(11):4739-49). Additionally, the PPARα pathway is critical for imparting a regulatory phenotype in intestinal macrophages. PPARα deficiency in mice led to commensal dysbiosis in the gut, resulting in a microbiota-dependent increase in the expression of inflammatory cytokines and enhanced susceptibility to intestinal inflammation. Pharmacological activation of this pathway decreased the expression of inflammatory cytokines and ameliorated colonic inflammation (J Immunol. 2016, 195 (11):4739-49). Taken together, these findings identify a new important innate immune function for the PPARα signaling pathway in regulating intestinal inflammation, mucosal immunity, and commensal homeostasis. Thus, the manipulation of the PPARα pathway could provide novel opportunities for enhancing mucosal immunity and treating colitis and colitis-associated colon cancer.

David H. Munn, MD

Research in the Munn laboratory is focused on the molecular mechanisms of immune suppression and tolerance in the tumor microenvironment. Major focus areas in the laboratory include (i) activation of suppressive tumor-associated Tregs via the PTEN lipid-phosphatase pathway; (ii) regulation of the dendritic-cell population in tumors, and the choice between tolerogenic versus immunogenic dendritic cells; and (iii) tolerance induction to dying tumor cells mediated via the enzyme indoleamine 2,3-dioxygenase (IDO) and PTEN+ Tregs. Basic-science studies of the role of the PTEN-phosphatase pathway in Tregs, including the regulation of the suppressor phenotype versus destabilization and reprogramming during inflammation, have been reported recently (Curr Opin Immunol. 2016,39:1-6), and in 2016 the Munn laboratory and Augusta University Research Institute (AURI) announced a joint agreement with NewLink Genetics Corporation to develop novel small-molecule drugs targeting the PTEN pathway in Tregs for cancer immunotherapy. The focus on the molecular mechanisms of inflammation-induced differentiation of immunogenic dendritic cells, and developing small-molecule drugs that induce differentiation of these cells in tumors, is aimed toward ultimately creating clinically applicable synergistic combinations of immunotherapy and chemotherapy. The first of these chemo-immunotherapy combinations is now in Phase I and Phase II clinical trials, using the IDO-inhibitor drug indoximod (Trends Immunol. 2016,37:193207), in combination with chemotherapy, radiation and checkpoint blockade. These trials are on-going in adult patients with pancreatic cancer, melanoma and glioblastoma multiforme (reported in ASCO Annual Meeting 2016, Abstracts 3075 and 3020, and Neuro-Oncology. 2016,18(suppl 6):vi13-vi4), as well as in first-in-children trials for pediatric brain tumors, in conjunction with Dr. Theodore Johnson and the Pediatric Immunotherapy service (Pediatr Blood Cancer. 2016,63:S72-S73).

In addition, the Munn laboratory collaborates closely with Dr. Bruce Blazar at the University of Minnesota (Blood. 2016,128:1013-7, Blood. 2016,128(10):1424-35, J Clin Invest. 2016,126:2642-60) as well as within the Georgia Cancer Center with the laboratories of Drs. Santhakumar Manicassamy (Oncoimmunology. 2016,5:e1115941), Gang Zhou (Oncoimmunology. 2016,5:e1171445), Andrew Mellor (Cancer Res. 2016,76:2076-81, PLoS Pathog. 2016,12:e1005615) and Nagendra Singh (Oncogenesis.

2016,5:e238).

Cancer immunology, Inflammation, & Tolerance

Senior Advisor to the Cancer Center Director Professor

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Paulo C. Rodriguez, PhD

Cancer immunology, Inflammation, & Tolerance

Associate Professor

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The long-term goal of the Rodriguez laboratory is to develop innovative strategies that restore protective immunity in cancer, leading to long-lasting anti-tumor effector T cell responses. As such, this group is currently focused on developing novel strategies to render T cells resistant to the suppressive tumor microenvironment and to metabolically reprogram highly tolerogenic myeloid-derived suppressor cells (MDSCs) into myeloid cells with the ability to induce immunogenic anti-tumor responses. In a recent report, Dr. Rodriguez’s group showed the surprising therapeutic effect of conditioning activated CD8 + T cells with tumor-infiltrating MDSCs before the adoptive T cell-based immunotherapy (ACT). They found that T cells pre-exposed to MDSCs induced an increased anti-tumor effect, which correlated with a higher persistence of the transferred T cells and elevated IFNγ production. This effect was mediated through the induction of T cell stemness in the MDSC-conditioned T cells, which was induced through inhibition of signaling through the mammalian/mechanistic target of rapamycin (mTOR) (Oncotarget. 2016, 7:17565). These results contribute to the development of strategies to increase ACT responses in cancer by making T cells resistant to tumors. Moreover, Dr. Rodriguez has collaborated with a team of leaders in the MDSC field to propose an algorithm for a precise definition of MDSCs in tumors (Nat Commun.

2016, 7:12150). This is expected to provide clarity in the identification of this important immune subset in tumors.

The Rodriguez laboratory is also interested in understanding the metabolic pathways that polarize MDSCs into highly tolerogenic cells in tumors. As such, they are actively collaborating with Dr. Augusto Ochoa’s group at Louisiana State University to understand the effect of lipid metabolism in the immunosuppressive polarization of MDSCs in cancer (Oncoimmunology. 2016, 5:e1200771). Continuation of this research is expected to enable the metabolic reprogramming of MDSCs into immunogenic myeloid cells, thereby serving as a major adjuvant for current immunotherapies.

Nagendra Singh, PhD

The long-term research focus of the Singh laboratory is to study how interaction between dietary fiber and gut microbiota influences intestinal inflammation and carcinogenesis. It was shown that the number of Bifidobacterium (good gut bacteria) is decreased and that of Prevotellaceae (bad gut bacteria) is increased in colon cancer tissue versus matched adjacent normal tissue from the same colon. In an animal model, Bifidobacterium suppressed colon carcinogenesis. Moreover, dietary fiber increased the number of Bifidobacterium and suppressed the abundance of Prevotellaceae in the colon (Oncogenesis. 2016, 5:e238). Thus, dietary fiber promoted good gut bacteria and suppressed bad gut bacteria such as Prevotellaceae. Mechanistically, the ability of dietary fiber to change the ratio of gut bacteria in favor of good gut bacteria is dependent on GPR43, which binds to acetate, propionate, and butyrate (collectively called short chain fatty acids or SCFAs), which are breakdown products of dietary fiber in colon. A review article about the beneficial role of SCFA receptors has been published (Pharmacol Ther. 2016, 164:144).

Recent studies by several laboratories have shown that an interaction between dietary fiber and gut microbiota plays a critical role in carcinogenesis. Understanding the molecular mechanisms regulating the effect of gut microbiota and diet on intestinal carcinogenesis and obesity will be very important in designing new therapeutic strategies aimed for prevention and /or treatment for these diseases.

Cancer immunology, Inflammation, & Tolerance

Assistant Professor

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Gang Zhou, PhD

Cancer immunology, Inflammation, & Tolerance

Associate Professor

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The Zhou laboratory studies how to combine standard-of-care chemotherapy and CD4+ T cell-based immunotherapy in a synergistic manner to treat cancer. The functional status of CD4+ T cells is a critical determinant of anti-tumor immunity. Polyfunctional CD4+ T cells possess the ability to concomitantly produce multiple Th1-type cytokines, exhibiting a functional attribute desirable for cancer immunotherapy. However, the mechanisms by which these cells are induced are undefined, and it is unclear if these cells can be used therapeutically to treat cancer. In a study published in OncoImmunology (2016, 5 (6):e1171445), they reported that CD4+ T cells exposed to exogenous IL-7 during antigenic stimulation can acquire a polyfunctional phenotype, characterized by the ability to simultaneously express IFNď §, IL-2, TNFÎą and granzyme B. Importantly, adoptive transfer of polyfunctional CD4+ T cells following lymphodepletive chemotherapy was able to eradicate large established tumors. This beneficial outcome was associated with the occurrence of antigen epitope spreading, activation of the endogenous CD8+ T cells, and persistence of donor CD4+ T cells exhibiting memory stem cell attributes. These findings indicate that IL-7 signaling can impart polyfunctionality and stemness potential to CD4+ T cells, revealing a previously unknown property of IL-7 that can be exploited in adoptive T cell immunotherapy.

Dr. Zhou has also collaborated with Georgia Cancer Center colleague, Dr. Feng-Ming Kong, to investigate combined stereotactic body radiation therapy and immunotherapy using the 4T1 triple-negative breast cancer murine model (Int J Radiat Oncol Biol Phys. 2016, Oct 1;96(2):E583.)

In addition, based on their recent study on the immunostimulatory effect of melphalan, Dr. Zhou and colleagues reviewed the recent advances in understanding and utilizing the immunomodulatory effects of melphalan (Crit Rev Immunol. 2016, 36(2):179-91). The alkylating agent melphalan is used in the treatment of hematological malignancies, especially multiple myeloma. In the past, the usefulness of melphalan has been solely attributed to its cytotoxicity on fast-growing cancerous cells. The findings from the Zhou laboratory indicate that melphalan can foster an immunogenic microenvironment by inducing immunogenic cell death (ICD) to facilitate the expansion of infused tumor-reactive T cells, implying that melphalan can be used as a preparative chemotherapy for adoptive T cell therapy.

Molecular Oncology & Biomarkers OVERVIEW

The research interests of the program can be divided into three broad themes: genetics and epigenetics of cancer development and progression; cell stress and metabolism; and cancer cell metastasis. Collectively, these themes address important topics of tumor cell and molecular biology:           

Genome-wide analysis of epigenetic changes in cancer development as a tool to identify biomarkers for prediction of progression and prognosis The genetic basis of cancer development and progression through the roles of specific genes and pathways The genetic basis of metastasis underlying the roles of metastasis suppressor genes, metastasis promoting genes, and microRNAs involved in metastasis Cancer genomics in primary human tumors and mouse models of cancer using gene expression and Next-Generation Sequencing (NGS) sequencing Application of bioinformatics tools to study complex data sets The role of transcription factors in promoting cancer progression The role of oncogenes and glycoconjugates in cancer cell progression Analysis of heat shock chaperones and other stress proteins in cancer development and as targets for cancer therapies Investigations of natural products as preventative and therapeutic agents The role of obesity and metabolic changes in the development of cancer Medicinal chemistry approaches to the development of novel therapeutics

Research in this program uses a wide variety of state-of-the-art cell and molecular biology approaches to understand the fundamental events underlying tumorigenesis and to explore how this knowledge impacts the prediction of tumor progression and whether specific genetic changes affecting cancer development can guide targeted therapies, leading to investigator-initiated clinical trials. These studies are complemented by a variety of in vivo models for specific types of cancer and translational application of biomarker studies using human materials facilitated by the Georgia Cancer Center Tumor Biorepository.

Molecular Oncology & Biomarkers

The overall goals of the Molecular Oncology & Biomarkers (MOB) Program are to understand the fundamental cellular and molecular processes that contribute to cancer development and progression.

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Molecular Oncology & Biomarkers MOB Program Members

Molecular Oncology & Biomarkers

MOB Program Member

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Laboratory Focus

Satyanarayana Ande, PhD

Understanding the molecular mechanisms of liver cancer, cancer cachexia, and metabolism/obesity

Ahmed Chadli, PhD

Understanding the biology and clinical implications of molecular chaperones, focusing specifically on the Hsp90 machine

John K. Cowell, PhD, DSc, FRCPath

The function of the WASF3 gene, which has been shown to promote metastasis in a variety of cancer cell types, and on ways to inactivate it to suppress invasion and metastasis

Quansheng Du, PhD

The molecular mechanisms underlying mitotic spindle organization, which is critical for accurate cell division

Zhonglin Hao, MD, PhD

Lung cancers, molecular genetics, modulation of the immune microenvironment, and searching for new drugs or drug combinations that are potentially promising in replacing traditional chemotherapy

Lesleyann Hawthorn, PhD

Global genetic profiling of cancers and cancer patients

Anatolij Horuzsko, MD, PhD

Understanding the role of Triggering Receptor Expressed on Myeloid cell 1 (TREM-1) in chronic inflammation and cancer

Hasan Korkaya, DVM, PhD

Understanding the molecular pathways that drive breast cancer stem cells

Iryna O. Lebedyeva, PhD

Discovery of chemical compounds that would be useful in the treatment of cancer

Balakrishna L. Lokeshwar, PhD

Chemokines and CXC-chemokine receptors in prostate cancer; using anti-cancer compounds found in edible plants to develop novel diagnostics and therapeutics

Vinata B. Lokeshwar, PhD

Biomarker-driven targeted therapy; novel diagnostic and prognostic tumor markers

MOB Program Members (continued) Laboratory Focus

Nahid F. Mivechi, PhD

Heat shock factors (HSFs) and cellular stress responses

Dimitrios Moskofidis, MD

Basic mechanisms of viral pathogenesis and of chaperone-mediated cancer promotion

Mumtaz V. Rojiani, PhD

The role of the tumor microenvironment in brain metastasis; the role of matrix metalloproteinases and their natural endogenous inhibitors, the TIMPs

Huidong Shi, PhD

Genomic, epigenomic, and proteomic approaches to identify novel mechanisms involved in the pathogenesis of chronic lymphocytic leu-

Yong Teng, PhD

Elucidate the cancer metastatic signaling cascade and establish animal disease models

Jan Van Riggelen, PhD

Epigenetic aspect of self-renewal and cellular differentiation in cancer; how the functional properties of transcription factors that determine cell fate are dependent on the epigenetic state of the cell

Daqing Wu, PhD

Develop novel therapeutic strategies for the treatment of prostate cancer bone metastasis

Wei-Hua Wu, PhD

How ATP-dependent chromatin remodeling enzyme alters chromatin structure to regulate gene expression

Chunhong Yan, PhD

Elucidate the roles of the stress sensor ATF3 in the cellular stress response and in cancer

W. Andrew Yeudall, PhD

Molecular pathogenesis of upper aerodigestive tract (head/neck and lung) cancers

Molecular Oncology & Biomarkers

MOB Program Member

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Satyanarayana Ande, PhD

Molecular Oncology & Biomarkers

Assistant Professor

The Ande laboratory focuses on understanding the molecular mechanisms of liver cancer, cancer cachexia, and metabolism/obesity. Liver cancer has just surpassed stomach cancer, becoming the second leading cause of cancer deaths worldwide. Metabolic reprogramming is one of the central hallmarks of cancer, and the majority of cancer cells, including liver cancer cells, depend on high rates of glycolysis and glutaminolysis for their growth and survival. The Ande laboratory identified that the transcriptional regulator inhibitor of DNA binding 1 (Id1) is strongly expressed in human liver tumor samples and that it promotes both glycolysis and glutaminolysis by regulating c-Myc levels through the MAPK/ERK pathway in HCC cells. Knock-down of Id1 prevented cancer cell metabolic adaptation and inhibited liver cancer cell growth (FASEB J. 2016, 30(1):262-75). Further investigations are under way to define the specific function of Id1 in liver tumorigenesis by using an Id1 knock-out mouse model, aiming to identify whether Id1 functions as a molecular target to inhibit liver tumor growth by blocking cancer cell metabolic reprogramming. In a separate ongoing study, Dr. Ande’s laboratory discovered that the transmembrane cell polarity protein Scrib can translocate to the nucleus in liver cancer cells and that it functions as a tumor suppressor. Their studies revealed that Scrib suppresses three oncogenes – Yap1, c-Myc and cyclin D1 – and that loss of Scrib significantly enhances liver tumor growth (Oncogene, In Press). Together, these studies have important implications in the understanding of molecular mechanisms of liver cancer.

Cancer cachexia is a complex condition of tissue wasting that affects up to 80% of cancer patients. To date, there is no effective treatment for cachexia due to the complex nature of this condition. Hypermetabolic activity and energy wasting in cachexia is predominantly caused by futile metabolic cycling, such as glucose recycling between the liver and tumor, and excessive lipid and protein turnover in the body. Another factor that significantly contributes to energy wasting in cachexia is browning of white adipose tissue (WAT). Therefore, identifying and inhibiting factors that promote glucose and lipid recycling and WAT browning can reduce energy wasting and ameliorate cachexia in cancer patients. In one of the ongoing projects, Dr. Ande’s laboratory discovered that Zinc-α2-glycoprotein (ZAG) promotes WAT browning and causes energy wasting in a mouse model. To further investigate the specific function of ZAG in cachexia-associated energy wasting, the Ande laboratory generated Rosa-26 locus-specific ZAG transgenic mice. In collaboration with Dr. Thomas Albers (Augusta University), they are also in the process of identifying small molecule inhibitors against ZAG, aiming to block ZAG-mediated energy wasting and treat/delay cachexia.

Dr. Ande’s laboratory is also interested in identifying genes/factors that promote obesity. The Id1 transcription factor has been shown to play a predominant role in brown adipose tissue (BAT) and functions as a negative regulator of the PGC1α/UCP1 thermogenesis pathway, thereby promoting obesity. Using an adipose tissue-specific Id1 transgenic mouse, it has been shown that adipose-specific overexpression of Id1 causes obesity. Id1 directly interacts with PGC1α and Ebf2, the central regulators of BAT thermogenesis and WAT browning, and suppresses their transcriptional activity. Overall, studies in the Ande laboratory have significant implications in the treatment of liver cancer, cachexia, and obesity.

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John K. Cowell, PhD, DSc, FRCPath

Major projects in the Cowell laboratory focus on the function of the WASF3 gene, which has been shown to promote metastasis in a variety of cancer cell types, and on ways to inactivate it to suppress invasion and metastasis. The laboratory has previously demonstrated that WASF3 phosphoactivation is required for transmitting metastasis signals from growth factor receptors and cytokines through the NFkB pathway, leading to increased invasion. WASF3 stability is maintained through an interaction with a group of proteins that includes NCKAP1 and CYFIP1 – the WASF3 regulatory complex (WRC). They have shown that genetic knockdown of NCKAP1 leads to suppression of metastasis by destabilizing the complex and suppressing WASF3 function (Cancer Res. 2016, 76:5133-42). NCAKP1, however, does not bind directly with WASF3. Through analysis of the crystal structure of the WRC, several interacting alpha helical surfaces were identified between NCKAP1 and CYFIP1, and stapled peptide mimics designed to target these interactions were developed. Treatment of breast, colon and prostate cells with these stapled peptides identified one, WANT3, that led to destabilization of the WASF3 protein with a resultant loss of invasion.

These peptides complement the WHAM1 peptide described previously that targets WASF3-CYFIP1 interactions. These peptides are being developed as therapeutic strategies to suppress metastasis.

A second project involves the characterization of the chimeric FGFR1 kinases associated with stem cell leukemia/lymphoma (SCLL). Chromosome translocations in this syndrome lead to myeloproliferation developing into acute myeloid leukemia (AML), with coincident T and B cell lymphomas, depending on the specific chimeric gene generated by the chromosome rearrangement. In attempts to better understand the genetic events that promote progression of leukemic stem cells to the different lineage disease, they have created a series of animal models in immunocompromised mice. Recently they developed a model that is representative of the most common chimeric kinase, ZMYM2-FGFR1, which shows myeloproliferation and AML after a 8-12 month latency period (Int J Cancer. 2016, 139:836-40) and demonstrates genetic changes that promote stemness and suppress differentiation.

Although constitutive activation of FGFR1 kinases is achieved through chromosome translocations in SCLL, analysis of gene expression databases showed that up to 20% of de novo AML also show overexpression of FGFR1. Targeting the fusion kinases in vivo using novel FGFR-specific drugs such as BGJ398 and AZT4547 indicated that leukemogenesis induced by cell lines carrying the activated FGFR1 kinase could be suppressed (Oncotarget. 2016, 7:49733-42). To study de novo AML, they created xenografts in immunocompromised mice with either overexpressed or normal FGFR1. Using BGJ398, leukemogenesis in the FGFR1-overexpressing AML was suppressed, but not in the non-overexpressing AML. These data suggest that targeting FGFR1 in overexpressing AML, regardless of the mechanism, could be considered as a therapeutic strategy for this subclass of AML. As part of the ongoing effort to develop murine models of human AML, they have now developed a humanized model in immunocompromised mice for AML driven by the t(6;9) chromosome translocation giving rise to the DEK-NUP214 fusion gene (Oncogene. 2016, 35(43):5686-91). This is one of the more aggressive subgroups of AML, and they now show the up-regulation of HOX genes, as well as other genes such as KRAS, BRCA1 and ALK, are associated with this disease. This model provides opportunities to develop therapeutic strategies to treat this subgroup of AML.

Molecular Oncology & Biomarkers

Co-Leader, MOB Program Georgia Cancer Center Associate Director, Basic Science Georgia Cancer Coalition Distinguished Scientist Professor

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Quansheng Du, PhD

Molecular Oncology & Biomarkers

Associate Professor

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The Quansheng Du laboratory is interested in the molecular mechanisms underlying mitotic spindle organization, which is critical for accurate cell division. They have uncovered a direct physical interaction between NuMA, an essential player in mitotic spindle assembly and maintenance, and Astrin, a spindleand kinetochore-associated protein. They show that the C-terminal tail of NuMA can directly bind to the C terminus of Astrin and that this interaction helps to recruit Astrin to microtubules (J Biol Chem. 2016, 291(38):20055-67). Knockdown of NuMA by RNA interference dramatically impaired Astrin recruitment to the mitotic spindle. Overexpression of the N terminus of the mammalian homologue of the Drosophila Pins (LGN), which blocks the microtubule binding of NuMA and competes with Astrin for NuMA binding, also led to similar results. Furthermore, they found that cytoplasmic dynein is required for the spindle pole accumulation of Astrin, and dynein-mediated transport is important for balanced distribution of Astrin between spindle poles and kinetochores. On the other hand, if Astrin levels are reduced, then NuMA does not efficiently concentrate at the spindle poles. Their findings reveal a direct physical link between two important regulators of mitotic progression and demonstrate the critical role of the NuMAAstrin interaction for accurate cell division.

Zhonglin Hao, MD, PhD

One research interest in the Hao laboratory focuses on modulation of the immune microenvironment in cancer. T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are suspected to be responsible for resistance to immune checkpoint inhibitors in cancer therapy (Onco Targets Ther. 2016, 9:5495-505). In a phase Ib/II investigator-initiated clinical trial supported by Merck and Gilead Sciences Inc, the Hao laboratory will test the first-in-its-class PI3K delta inhibitor idelalisib in lung cancer patients who have become refractory to immune checkpoint inhibitors in order to boost the objective response rate. A positive study would be the first proof that down-regulation of Tregs is a promising approach to overcome checkpoint inhibitor resistance.

Dr. Hao’s laboratory has also studied the mechanism of action of YM155, which was originally developed as a survivin inhibitor. They showed that YM155 functions not as a survivin inhibitor, but as an inhibitor of both topoisomerase I & II, and that it induces cell cycle arrest in G1/S or M and suppresses global transcription. Cells treated with YM155 harbor DNA damage, and these cells repair their DNA poorly, suggesting that the DNA damage is a result of defective DNA repair. YM155 is not able to chelate DNA. In vitro assays using recombinant TOPOI and TOPOII showed suppression of both enzyme activities by YM155 (Anticancer Drugs, in press).

In collaboration with Dr. Jin Xie (University of Georgia), a nanoparticle that was able to overcome the shallow penetrance of conventional photodynamic therapy (PDT) was successfully engineered and used for the treatment of cancers that reside deep within tissues (Theranostics. 2016 6(13):2295-2305). In this application, both radiation and PDT are used.

In an effort to capture circulating tumor cells (CTCs) from the blood stream, the Hao laboratory joined the Mao laboratory (University of Georgia) in isolating CTCs from metastatic lung cancer patients. With a self-made, low-cost device, they have successfully and reliably captured cancer cells using ferrofluid operating under a magnetic field. This liquid biopsy based on cell size has the promise of replacing Cell Search for CTC isolation, which is based on epithelial markers on the surface of CTCs. Epithelial to mesenchymal transition (EMT) often causes loss of epithelial markers.

Molecular Oncology & Biomarkers

Co-Leader, Thoracic Oncology Program Associate Professor

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Anatolij Horuzsko, MD, PhD

Molecular Oncology & Biomarkers

Associate Professor

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The main research focus of Dr. Horuzsko’s laboratory is to understand the role of Triggering Receptor Expressed on Myeloid cell 1 (TREM-1) in chronic inflammation and cancer. TREM-1 is a major player in the amplification and signaling of the inflammatory response. Dr. Horuzsko’s group reported a previously unknown role of TREM-1 in the initiation and progression of liver fibrosis, which is the major risk factor for the development of cirrhosis and hepatocellular carcinoma. They determined that TREM-1 enhanced liver fibrosis development and identified TREM-1 as a master regulator of Kupffer cell activation that controls the liver inflammatory response and the activation status of hepatic stellate cells. Dr. Horuzsko’s group is also interested in the metabolism of classically and alternatively activated macrophages and their role in liver damage.

In collaboration with Dr. L. Mulloy (Department of Medicine, Augusta University), the Horuzsko laboratory has studied innovative methods and therapies that prevent allograft rejection and prolong transplant survival in patients. They demonstrated that HLA-G expression is one of the critical factors in controlling immune responses in clinical transplantation. Dr. Horuzsko’s group reported for the first time that HLA-G dimers associate with prolonged human kidney allograft survival. A mouse model is currently under development for studying HLA-G functions in basic science and pre-clinical research. Humanized mouse models have been developed to determine the prognostic factors for acceptance of the human allogeneic kidney and for the optimization of therapy to prolong allograft survival (Human Immunology. 2016, 77:711-719). These studies offer novel approaches to achieve reproducible transplantation tolerance and to develop personalized medicine to prevent allograft rejection.

Hasan Korkaya, DVM, PhD

The main focus of Dr. Hasan Korkaya’s laboratory is to understand the molecular pathways that drive breast cancer stem cells (CSCs). Notch signaling is a developmental pathway that plays a critical role in embryonic- and tissue-specific stem cell maintenance. The Korkaya group has utilized the Notch reporter system to determine the role of Notch activity in breast and lung CSC maintenance. In vitro and mouse xenograft data demonstrated that the Notch pathway is a critical driver of breast and lung CSCs since breast and lung cancer cells with higher Notch activity show tumor initiation capacity in mouse xenografts. Furthermore, they show that a gamma secretase inhibitor (inhibitor of Notch pathway) effectively targets breast CSCs in vitro and in mouse xenograft models.

EGFR and cMET amplification/overexpression account for 15-20% of breast cancers and are associated with the triple negative breast cancer subtype, which displays the most aggressive/metastatic phenotype. In recent collaborative studies with Dr. Carrie Graveel (Van Andel Research Institute, Grand Rapids, MI), the Korkaya laboratory demonstrated that simultaneous targeting of these two oncogenic pathways results in superior efficacy compared to a single drug alone, suggesting that breast cancer patients with the triple-negative subtype may benefit from this drug combination (Oncotarget. 2016, 7(43):69903-15).

In collaboration with Dr. Fayaz Malik at the Indian Institute of Integrative Medicine, Korkaya’s group recently demonstrated that the boswellic acid analog BA145 induces autophagy via arresting pancreatic cancer cells at the G2/M phase. Surprisingly, induction of autophagy was reversible and cells survived when the signal is averted, suggesting a survival mechanism for pancreatic tumor cells under stress. They also demonstrated that induction of autophagy by BA145 resulted in suppression of the mTOR pathway and rebound in AKT phosphorylation (Sci Rep. 2016, 6:33146).

Molecular Oncology & Biomarkers

Assistant Professor

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Iryna O. Lebedyeva, PhD

Molecular Oncology & Biomarkers

Assistant Professor

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The main research goal of the Lebedyeva laboratory is the discovery of chemical compounds that would be useful in the treatment of cancer. The Lebedyeva laboratory has participated in intra- and interprogrammatic projects to facilitate the development of compositions for modulating PD-1 signal transduction (U.S. Provisional Application 62/429,126, 12/2/2016) and novel analogs of ceramide that provide FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes (Sci. Reports. 2016, 6:30816-21; Oncotarget. 2016, DOI: 10.18632/ oncotarget.13438). Studies involving magnetic nanoparticles have suggested a new approach to improve the efficacy of gene therapy against differentiated human uterine fibroid cells and tumor-initiating stem cells (Fertil Steril. 2016, 105(6):1638-48). A collaborative project on the development of diazapentacene derivatives has also been reported recently (RSC Advances. 2016, 6:86824-28). In a collaborative effort exploring the lectin-like domain of TNF and its increase of ENaC suggested a novel site at the interface between the second transmembrane and C-terminal domains of the alpha subunit (J Biol Chem. 2016, doi: 10.1074/jbc.M116.718163). In collaboration with Dr. Paul Dent (Virginia Commonwealth University), two projects supporting repurposing of anti-cancer drugs have been presented (Oncotarget. 2016, 7 (26):40398-417; Oncotarget. 2016, 7(11):12975-96).

Balakrishna (Bal) L. Lokeshwar, PhD

Dr. Bal Lokeshwar and his group are engaged in two areas of cancer research to develop novel diagnostics and therapeutics for prostate, bladder and breast cancers. The first area is to develop targeted cancer prevention using anti-cancer compounds found in edible plants and combining them to enhance existing systems of therapy, such as chemotherapy. The group has reported anti-cancer activity of compounds present in an edible spice, Pimenta dioica (allspice), against prostate and breast cancers. These compounds selectively killed breast cancer cells in culture dishes and slowed the growth of aggressive, metastatic breast cancer in animal models. The group reported the anti-cancer activity of a South American plant-derived supplement (BIRM) that specifically kills prostate cancer cells by accelerated degradation of the androgen receptor in localized prostate cancer models. BIRM had no toxic effect in mice used to generate in vivo models of prostate cancer (Oncotarget. 2016, PMID: 27705939). Ongoing work in the laboratory towards identifying the anti-tumor compounds from allspice has led to the identification of new anti-proliferative compounds and to the synthesis of more potent analogs of Ericifolin, an antiprostate cancer compound. Synthetic compounds resembling natural compounds showed higher affinity to the targets on cancer cells.

The second area of research focus is chemokines and CXC-chemokine receptors as survival factors in prostate cancer. The atypical CXC-chemokine receptor CXCR7 is the latest of the 7-transmembrane receptor family to be characterized. These receptors play a pivotal role in prostate cancer cell survival following androgen deprivation, and they signal through a growth factor receptor (EGFR). The Bal Lokeshwar group reported that CXCR7 complexes with EGFR to enhance EGFR-EGF-mediated growth of tumor cells. In addition, CXCR7-EGFR receptors co-localize to the cell nucleus, putatively resulting in enhanced cell proliferation and potentially increasing the metastatic potential of tumor cells. Further, the CXCR7-EGFR interaction is regulated by the structural (scaffold) protein β-arrestin 2 in prostate cancer (Mol Cancer Res. 2016, 14(5):493-503). Their recent review article highlighted the importance and potential application of natural, anti-cancer products in the prevention of castration-resistant prostate cancer (Semin Cancer Biol. 2016, 40-41:160-9).

In summary, the ongoing work in the laboratory has focused on the role of CXCR7 and β-arrestins in chemoresistance and the use of CXCR7 as a biomarker for bladder cancer progression, metastasis and resistance to common chemotherapeutics. The laboratory employs CRSPR-Cas9 gene editing technology, treatment-refractory cancer stem cell characterization, and transgenic and human PDX models to identify novel prognostic biomarkers, targets of natural anti-cancer products, and mechanisms of tumor progression.

Molecular Oncology & Biomarkers

Co-Director, Natural Product Cancer Initiative and Biochemistry & Cancer Biology Training Program Dr. J. Harold Harrison Distinguished University Professor Professor

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Vinata B. Lokeshwar, PhD

Molecular Oncology & Biomarkers

Department Chair, Biochemistry & Molecular Biology Professor

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Vinata Lokeshwar’s laboratory focuses on biomarker-driven targeted therapy and is investigating mechanisms of bladder, prostate, and renal cell carcinoma progression to discover novel diagnostic and prognostic tumor markers and to develop targeted cancer therapeutic and chemopreventive strategies. The laboratory examines how hyaluronic acid (HA), a glycosaminoglycan, and the hyaluronidase (HAase) family of molecules promote tumor growth, metastasis, and angiogenesis. They were one of the first to connect HAase, an endoglycosidase that degrades HA, to tumor biology, and the first to identify and characterize HYAL-1 as a tumor-derived HAase. Their work demonstrating that the tumor-associated HA-HAase system promotes tumor growth and progression has identified this system as a target in cancer therapy.

They identified that sulfated-HA (sHA) is a potent inhibitor of HYAL-1 HAase activity and previously demonstrated that sHA has potent anti-tumor activities in preclinical models of prostate cancer. Recent work shows that small molecular derivatives of sHA have potent anti-tumor activity in preclinical models of bladder cancer (Oncotarget. 2016, doi: 10.18632/oncotarget.10529). Mechanistic studies reveal that the tumor HA-HAase system induces HA-receptor-mediated signaling that involves CD44-mediated activation of phosphoinositide 3-kinase (PI3-K) and AKT. Consequently, major effectors of the CD44-PI3-K/ AKT pathway are the up-regulation and activation of epithelial mesenchymal transition (EMT) markers.

By targeting HYAL-1 activity, sHA inhibits tumor-associated HA signaling with potent anti-tumor activity.

Regarding cancer biomarkers, the laboratory has demonstrated that HYAL-1, alone or with HA, predicts metastasis and disease-specific survival in bladder cancer patients and biochemical recurrence in prostate cancer patients. Their recent work shows that HA-family markers, including HA synthases and HYAL1, as well as certain EMT markers, either individually or together, are predictors of metastasis and disease-specific mortality in bladder cancer patients. Moreover, there is a correlation between the expression of HA-family and EMT markers in bladder cancer patients, supporting the laboratory’s mechanistic studies showing that by regulating EMT and associated signaling, the tumor-associated HA-HAase system controls tumor cell functions. In the area of targeting of HA for cancer chemoprevention and therapy, the laboratory has evaluated the anti-cancer properties of 4-MU, a small molecule inhibitor of HA synthesis. They demonstrated that 4-MU is a potent chemopreventive and therapeutic agent that prevents and eliminates prostate cancer development, growth, and bone/soft tissue metastasis in transgenic and bone metastasis models. Mechanistic studies showed that 4-MU specifically inhibited HA signaling in prostate cancer cells. By targeting HA-HA receptor interactions and subsequent PI3-K/AKT and EMT signaling, 4-MU displays potent anti-tumor activity in preclinical models of bladder cancer. They are currently using 4-MU and FDA-approved treatments for the control of metastatic renal cell carcinoma. The laboratory is also studying a novel member of the hyaluronidase family that induces the cancer stem cell phenotype and chemoresistance in preclinical models of bladder cancer; its expression and activity is potentially a non-invasive diagnostic marker for bladder cancer, with prognostic capabilities to predict metastasis and disease-specific mortality. Another project involves functional studies on a potential tumor suppressor in renal cell carcinoma. They discovered this gene through differential gene expression analyses on clinical specimens and found that its expression correlates with racial disparity associated with renal cell carcinoma and clinical outcome. They hope this research will contribute to the development of individualized treatment strategies for urological cancers that are based on biomarker expression in a patient’s tumor.

Nahid F. Mivechi, PhD

The laboratory of Nahid Mivechi is interested in heat shock factors (HSFs) and cellular stress responses.

Metabolic energy reprogramming facilitates adaptations to a variety of stress conditions and cellular dysfunction, but how the energetic demands are monitored and met in response to physiological stimuli remains elusive. Data from the Mivechi laboratory support a model demonstrating that heat shock factor 1 (HSF1), a master transcriptional regulator of the chaperone response, has been co-opted from its role as a critical protein quality-control regulator to having a central role in systemic energy sensing and for metabolic adaptation to nutrient availability. It has been shown that in the absence of HSF1, levels of NAD+ and ATP are not efficiently sustained in hepatic cells, primarily due to transcriptional repression of Nampt in the NAD+ salvage pathway. Mechanistically, the defect in NAD+ and ATP synthesis linked to a loss of NAD+-dependent deacetylase activity, increased protein acetylation, and impaired mitochondrial integrity. Remarkably, the drop in ATP level caused by HSF1 loss invoked an adaptive response featured by inhibition of energetically demanding processes, including gluconeogenesis, translation and lipid synthesis. This work identifies HSF1 as a central regulator of cellular bioenergetics and protein homeostasis that benefits malignant cell progression and exacerbates development of metabolic diseases (J Cell Biol, in press).

Molecular Oncology & Biomarkers

Co-Leader, MOB Program Professor

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Huidong Shi, PhD

Molecular Oncology & Biomarkers

Georgia Cancer Coalition Distinguished Scholar Professor

The Shi laboratory uses genomic, epigenomic, and proteomic approaches to identify novel mechanisms involved in the pathogenesis of chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults. Despite advancements in treatment regimens over the past decade, CLL remains incurable.

Many expression landscape studies have been pursued to better understand CLL pathogenesis. However, the underlying molecular mechanism of the altered transcriptome in CLL remains elusive. To better comprehend the differential epigenetic changes that take place in CLL, the Shi laboratory performed integrated analysis of DNA methylation and gene expression using genome-wide DNA methylation and mRNA sequencing in 52 CLL patient and healthy control samples. A large number of differential methylation changes, both hypo- and hypermethylation, appear to be common in CLL. Interestingly, hypomethylation appears to play an active, targeted, and complementary role in cancer progression, and interplays with hypermethylation in a coordinated fashion in the regulation of key pathways, such as the B cell receptor and p53 pathways, and genes/motifs essential for B lymphopoiesis (Hum Genomics. 2016, 10 Suppl 2:18.). Furthermore, DNA hypomethylation is enriched in B cell enhancer and super-enhancer regions, resulting in activation of immune and metabolic pathways in CLL. The Shi laboratory demonstrated that small molecule inhibitors targeting super-enhancer genes can induce apoptosis and inhibit cell proliferation by modifying the metabolic capacity of CLL cells.

One of the problems faced by CLL patients is that the leukemic cells induce a state of immunosuppression that causes increased susceptibility to infections and failure of anti-tumor immune responses. Immune dysfunction and the resultant increased incidence of infectious complications accounts for 50 percent of all deaths in patients with CLL. In collaboration with clinicians at Nanjing Medical University in China, Dr Shi’s group also investigated epigenetic reprogramming in T cells from CLL patients (Oncotarget. 2016, 7:40558-40570). Using a genome-wide DNA methylation array, it was shown that immune regulatory genes are differentially methylated in CD8 + T cells from CLL patients as compared with normal donors, suggesting epigenetic reprogramming influences immune dysfunction in CLL. Mechanistically, the Shi laboratory identified a regulatory region of the PD-1 receptor, which is an immune checkpoint protein and an important target of current immunotherapy. The PD-1 regulatory region, approximately 4.7 kb upstream from the transcription start site, was shown to be hypomethylated in CD8+ T cells from CLL patients and may serve as an enhancer under the influence of CpG methylation.

In addition, Dr. Shi has collaborated with Drs. Hang Shi and Bingzhong Xue at Georgia State University to study epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity (JCI Insight. 2016,1: e87748). The Shi laboratory has also collaborated with several groups of statisticians and bioinformaticians to develop computational methods and algorithms for detecting differential methylation (Stat Appl Genet Mol Biol. 2016, 15:237-51) and predicting CpG methylation status based on genome topological features and deep networks (Sci Rep. 2016, 6:19598).

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Yong Teng, PhD

The main research focus of Dr. Teng’s laboratory is to elucidate the cancer metastatic signaling cascade and establish animal disease models. In the past few years, Dr. Teng and his collaborators have successfully identified several novel targets and signaling pathways that control cancer cell growth, invasion and metastasis. In a recent report, Dr. Teng’s group has identified that ADP-ribosylation factor 1 (ARF1) promotes prostate tumorigenesis via targeting oncogenic MAPK signaling (Oncotarget. 2016, 7(26):3983445). These data demonstrate that aberrant MAPK signaling in prostate cancer is, at least in part, under the control of ARF1 and that, similar to Ras, ARF1 is a critical regulator in prostate cancer progression. They further reported that ARF1 is the most amplified gene of the ARF gene family in breast cancer, and high-level amplification of ARF1 is associated with increased mRNA expression and poor outcomes of patients with breast cancer. Loss of ARF1 expression in breast cancer cells inhibits pulmonary metastasis, and inactivation of ARF1 suppresses metastatic dissemination of breast cancer cells (Oncotarget.

2016, doi:10.18632/oncotarget.11185). These findings underscore the importance of ARF1 in promoting metastasis and suggest that inhibition of ARF1 may represent a potential therapeutic approach to prevent or treat breast cancer metastasis. In addition, Dr. Teng has collaborated with Dr. John Cowell (Georgia Cancer Center) and with other universities to seek novel metastatic signaling molecules and develop novel anti-cancer strategies, such as using stapled peptides to suppress breast cancer metastasis (Cancer Res. 2016,76:965-73; Cancer Res. 2016, 76(17):5133-42; Oncogene 2016, 35(3):333-43; Oncogene 2016, 35(35):4633-40), and a cocktail of MEK1/2 and Src inhibitors against ovarian cancer progression (Oncogene 2016, doi: 10.1038/onc.2016.323). These studies provide therapeutic windows for combating advanced cancers.

Molecular Oncology & Biomarkers

Assistant Professor

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Daqing Wu, PhD

Molecular Oncology & Biomarkers

Associate Professor

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The main research interest of Dr. Wu’s laboratory is to develop novel therapeutic strategies for the treatment of prostate cancer bone metastasis. In a recent study, Dr. Wu’s group identified BKM1644, a bisphosphonate-conjugated small-molecule compound, as a potential candidate for the treatment of bone metastatic prostate cancer. BKM1644 is potently cytotoxic against the NCI-60 panel of human cancers and sensitizes prostate cancer cells to docetaxel by inhibiting the expression of survivin via a Stat3dependent mechanism. In a pre-clinical mouse model of skeletal tumors induced by prostate cancer cells, BKM1644 yielded significantly lower prostate-specific antigen levels, increased apoptosis and reduced survivin. These results suggest that the anti-survivin compound BKM1644 may provide a strategy for improving the current standard of care for prostate cancer patients with bone metastasis (Oncotarget. 2016 7:27489). Dr. Wu’s group also developed a novel nutraceutical formulation (ProFine®) that demonstrates effectiveness in suppressing prostate tumor growth in mouse models and in extending the survival of tumor-bearing animals. This formula can provide a safe, affordable and effective alternative therapy for both low-risk and advanced prostate cancer patients (U.S. Patent Application 15/279,866, 2016).

Dr. Wu’s laboratory collaborated with Drs. HongYan Liu and Jin-Xiong She at the Center for Biotechnology and Genomic Medicine, Augusta University, to develop a bivalent aptamer-dual siRNA chimera that efficiently targets both EGFR and survivin and inhibits the growth of prostate cancer in mice (Sci. Rep. 2016 6, 30346). In a collaboration with Dr. Jenny Yang at Georgia State University, Dr. Wu’s group evaluated the potential of prostate-specific membrane antigen-targeted protein contrast agents in the detection of prostate cancer using magnetic resonance imaging (MRI) (Nanoscale. 2016 8: 12668-82).

Chunhong Yan, PhD

A long-standing research interest of the Yan laboratory is the common stress sensor ATF3, where the research goal is to elucidate the roles of ATF3 in the cellular stress response and cancer. Although it has been known for a long time that ATF3 expression can be rapidly induced by DNA damage caused by UV irradiation, whether and how ATF3 induction determines cell fate under this carcinogenic condition remains largely unknown. In a recent report (J Biol Chem. 2016, 291:10847-57), Dr. Yan’s group showed that ATF3 can help cells to repair UV-induced DNA damage, thereby protecting cells from UV-caused death. While this effect was linked to an early finding that ATF3 can activate p53, they further demonstrated that ATF3 instead promotes UV-caused cell death in p53-mutated cells by regulating the stability of a pro-apoptotic protein, Tip60. ATF3’s dichotomous contributions to the cellular UV response are in line with the notion that ATF3 is essential for the maintenance of genome integrity and the suppression of cancer. Indeed, employing knockout mouse models, Dr. Yan’s group has demonstrated that ATF3 can prevent prostate cancer development in an experimental condition mimicking hormone imbalance in aging men (Oncogene. 2016, 35(27):3555-64). The latter finding is noteworthy, as aging is a major risk factor for prostate cancer. To further understand the role of ATF3 in the DNA damage response, the group also collaborated with Dr. Jindan Yu at Northwestern University and utilized integrated genomics approaches to investigate the ATF3-binding landscape at the genome level. They have revealed that ATF3 is pre-loaded onto genome sites and prime genes associated with these sites for expression upon DNA damage (BMC Genomics. 2016, 17:335). The latter results have provided further evidence supporting the importance of ATF3 in the regulation of the cellular response to DNA damage.

In addition, Dr. Yan has collaborated with Dr. Junran Zhang at Case Western Reserve University to study the regulation of BRCA1 in DNA repair (Oncogene. 2016, 35(11):1363-72) and develop a CHK1-targeted strategy for sensitizing radioresistant breast cancer cells to radiation therapy (Oncotarget. 2016, 7 (23):34688-702).

Molecular Oncology & Biomarkers

Associate Professor

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W. Andrew Yeudall, PhD

Molecular Oncology & Biomarkers

Department Chair, Oral Biology Professor

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The focus of Dr. Yeudall's laboratory is the molecular pathogenesis of upper aerodigestive tract (head/ neck and lung) cancers. In general, these tumors have a late clinical presentation and relatively poor prognosis. Additionally, many are refractory to treatment with standard chemotherapeutic regimens and develop resistance to targeted therapies. The goal of the laboratory is to understand common molecular mechanisms that drive progression of these cancers and to identify druggable targets. The laboratory has previously identified aberrations in the EGFR signaling pathway, as well as oncogenic gain-offunction (GOF) mutations in p53, both of which enhance growth and motility of cancer cells. In recent studies, they found that multiple gain-of-function mutant p53 alleles are able to up-regulate expression of the EGFR by localizing on the EGFR promoter region at a GOF p53 response element, enhancing chromatin opening and recruiting the transcription factors Sp1 and CBP (Oncotarget. 2016, 7:12426-46).

Transactivation by GOF p53 can also occur in the absence of a functional transactivation domain. The laboratory is also pursuing the development of nanoscale materials for tumor imaging and delivery of therapeutics. Tumor cells frequently overexpress the folate receptor compared to normal cells; thus, folate-conjugated dendrimer nanoparticles were developed and used to transduce squamous carcinoma cells (Nanomedicine. 2016, 11(22):2959-73). Folate-conjugated fluorescent nanoparticles were selectively taken up by tumor cells expressing high levels of folate receptor at high efficiency by receptormediated endocytosis, permitting high levels of transgene expression. These results suggest a potential for targeted delivery of therapeutics to tumor cells based on their cell surface protein expression profile, while minimizing effects on normal cells. In collaborative studies (Oncotarget. 2016, 7:36353-65) with Dr. Hisashi Harada's laboratory (Virginia Commonwealth University), the Yeudall laboratory reported p53-independent up-regulation of the pro-apoptotic protein Noxa in response to DNA-damaging agents as a key mediator of MCL-1 phosphorylation by CDK2, which is necessary for proteasomal degradation of MCL-1 and induction of apoptosis.

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Tumor Signaling & Angiogenesis OVERVIEW

Tumor Signaling & Angiogenesis

The unifying theme of the Tumor Signaling & Angiogenesis (TSA) Program is to build translational clinical trials based on innovative and novel research projects that focus on signaling cascades leading to uncontrolled cell growth and resistance to apoptosis. The program goals are to identify dysregulated molecular signaling pathways that can be used as cancer-specific targets. Collectively, the members of this program work cooperatively to study:

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       

A variety of kinase targets involved in cancer cell proliferation and progression The basic underlying mechanisms whereby a variety of membrane transporters promote cancer cell survival and how these can be targeted in therapeutic strategies Growth factors and lipid signaling molecules that stimulate growth and invasion The role of G protein-coupled receptors that are involved in a variety of cancer cell functions and metabolism Epigenetic regulation of biosynthetic pathways in cancer cell metabolism and proliferation The role of the MYCN oncogene in the development of pediatric tumors Novel regulators of apoptosis Mechanism of resistance to anti-angiogenesis treatments visualized in vivo using imaging approaches such as MRI and SPECT

Targets identified in this program can be exploited to develop innovative approaches to cancer prevention and therapy that can be translated into clinical trials. The research into cancer cell signaling incorporates animal models in breast and colon cancer, as well as the pediatric cancer neuroblastoma, to study how specific signaling pathways are involved in the progression of cancer and how targeting these pathways can be developed into novel therapeutic approaches.

TSA Program Members Laboratory Focus

Ali Arbab, MBBS, PhD

Determining the mechanisms of therapy resistance by focusing on the involvement of bone marrow-derived cells in modulating the tumor microenvironment and initiating tumor neovascularization in glioma and breast cancer models

Erhard Bieberich, PhD

The function of lipids in cancer cell signaling

Wendy B. Bollag, PhD, FAHA

Signals that regulate the proliferation and differentiation of epidermal keratinocytes, the predominant cells of the outer layer of the skin, and what goes wrong in cancer

Darren D. Browning, PhD

Developing novel cGMP-focused treatment strategies for gastrointestinal diseases

Han-Fei Ding, PhD

The role of histone methylation states in the transcriptional regulation of cancer metabolism

Ellen K. LeMosy, MD, PhD

How proteins and carbohydrates within the extracellular matrix (ECM) microenvironment regulate growth factor signals transmitted between cells

Honglin Li, PhD

The Ufm1 conjugation system, a novel ubiquitin-like protein modification system

Nita J. Maihle, PhD

Cancer therapeutics targeting the EGF/HER family of receptor tyrosine kinases

Betty Pace, MD

Develop strategies to induce fetal hemoglobin expression to block sickle hemoglobin polymerization and improve the clinical symptoms of sickle cell disease (SCD)

Daitoku Sakamuro, PhD

Cancer resistance mechanisms by which cancer cells tolerate cytotoxic stress signals, such as DNA damage and substratum dissociation

Patricia V. Schoenlein, PhD

Understanding the role of autophagy in breast cancer cells undergoing conventional therapies

Muthusamy Thangaraju, PhD

Understand the functional role of epigenetics, especially DNA methylation and histone modification, in the regulation of mammary stem and progenitor cells and of breast cancer stem cells

Guangyu Wu, PhD

Molecular mechanisms underlying the intracellular trafficking of G protein-coupled receptors

Tumor Signaling & Angiogenesis

TSA Program Member

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Ali Arbab, MD, PhD Leader, Tumor Angiogenesis Initiative Professor

Tumor Signaling & Angiogenesis

Therapy resistance is an emerging hallmark and daunting outcome for any adjuvant treatment in the clinic. Most adjuvant treatments have witnessed involvement of bone marrow-derived cells, causing therapy resistance and tumor relapse in a subset of patients.

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Dr. Arbab’s laboratory is devoted to determining the mechanisms of therapy resistance by focusing on the involvement of bone marrow-derived cells in modulating the tumor microenvironment and initiating tumor neovascularization in glioma and breast cancer models. To understand the involvement of bone marrow cells in developing resistance to anti-angiogenic therapies (AATs), chimeric animal models have been developed where the bone marrow of the recipient animal is replaced with GFP-expressing bone marrow cells. The accumulation of GFP+ bone marrow cells can be determined by in vivo optical imaging (Cancer Biol Ther. 2016,17(3):280-90). Dr. Arbab’s group documented that tumor-recruited bone marrow cells are predominantly a heterogeneous myeloid cell population that is able to predict therapeutic response in cancer (Onco Targets Ther. 2016, 9:1047-55). Several strategies to target bone marrow or tumor-promoting myeloid cells are being used to potentiate the anti-tumor effect of FDA-approved drugs in preclinical models of glioblastoma and breast cancer. In addition, Dr. Arbab’s group has successfully tested an IV formulation of the new drug HET0016 for the treatment of glioma and breast cancers (Onco Targets Ther. 2016 9; 9:1205-19).

In addition to tumor cell extrinsic mechanisms, tumor intrinsic mechanisms such as vascular mimicry are being actively investigated. Tumor cells, under the influence of therapeutic drugs, acquire endothelial cell-like characteristics through the mesenchymal cell state to enhance tumor vasculature and therapy resistance to cause relapse (Histol Histopathol. 2016, doi: 10.14670/HH-11-856). Recent studies identified that, following anti-angiogenic treatment, there is nuclear translocation of VEGFR2 in glioma (J Cancer Sci Ther. 2016, 8:172-178).

In collaboration with different investigators, Dr. Arbab has shown the utility of in vivo imaging in the identification of changes in internal organs in preclinical tumor studies (Cancer Res. 2016, 15;76(8):207681) and in the utility of a nanoparticle-based contrast agent in triple-negative breast cancer (J Nanomed Nanotechnol. 2016, 7(5): 1000404). In addition, in collaboration with various groups, the involvement of endothelial progenitor cells in rheumatoid arthritis is under study (Arthritis Res Ther. 2016, 18:87).

Wendy B. Bollag, PhD, FAHA

A long-standing research interest of the Bollag laboratory involves the signals that regulate the proliferation and differentiation of epidermal keratinocytes, the predominant cells of the outer layer of the skin, and what goes wrong in cancer. Non-melanoma skin cancers (NMSCs), primarily resulting from abnormalities in these cells, are the most common cancer in the world, with approximately three million new cases diagnosed each year in the United States alone. While most NMSCs are eminently remedied by surgical removal, treatment is often disfiguring. The etiology of NMSCs is not entirely understood, although the most important risk factor for these cancers is chronic sun exposure, i.e., ultraviolet (UV) radiation. The Bollag laboratory has previously shown that protein kinase D (PKD) levels are increased in the NMSC basal cell carcinoma and in neoplastic mouse keratinocytes. Furthermore, they demonstrated that PKD1 is activated by UV irradiation of mouse epidermal keratinocytes and that this activated PKD1 protects mouse keratinocytes from UV-induced apoptosis, suggesting a possible role for PKD1 in epidermal tumorigenesis. Further, it was shown that Cre adenovirus-mediated deletion of PKD1 in keratinocytes derived from PKD1-floxed mice inhibited their proliferation and stimulated differentiation. The mechanisms by which PKD1 regulates keratinocyte biology and skin function under both physiological and pathological conditions are under investigation. On the other hand, another signaling pathway of interest appears to exert the opposite effect and promotes keratinocyte differentiation. This pathway is composed of the aquaglyceroporin, aquaporin-3 (AQP3) and the lipid-metabolizing phospholipase D-2 (PLD2), which are physically and functionally associated in keratinocytes to produce the phospholipid, phosphatidylglycerol. The Bollag group has previously demonstrated that AQP3 and/or PLD2 levels (and/ or localization) are abnormal in NMSCs. The likely importance of this signaling module to keratinocyte and skin function has led to studies of its regulation. Recently it was shown that histone deacetylase inhibitors, which are in clinical trials for the treatment of some cancers, are able to increase AQP3 mRNA and protein expression. The histone deacetylase involved in this regulation and one potential mechanism by which it might affect AQP3 expression has been identified. Additional studies are under way to define AQP3’s regulatory mechanisms as well as the role of the AQP3-PLD2-PG signaling pathway in modulating skin function and susceptibility to disease.

Tumor Signaling & Angiogenesis

Professor

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Darren D. Browning, PhD

Tumor Signaling & Angiogenesis

Co-Director, Biochemistry & Cancer Biology Training Program Associate Professor

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The Browning laboratory is interested in developing novel cGMP-focused treatment strategies for gastrointestinal diseases. They have previously published evidence that specific phosphodiesterase-5 (PDE5) inhibitors such as sildenafil can increase cGMP levels in the intestinal epithelium and that this has dramatic effects on homeostasis. The resulting “cGMP-gut� has altered cellular composition and properties that confer resistance to toxic insults. In an effort to better understand the mechanism underlying the protective effect of cGMP on the gut epithelium, the laboratory has identified a novel endogenous system that protects the differentiated epithelium. This intestinal epithelial layer is exposed to redox stresses that arise from contact with the luminal contents, and this stress leads to activation of FoxO3a, a transcription factor that increases the expression of antioxidant protection enzymes in differentiated cells.

Increasing cGMP can activate FoxO3a-dependent antioxidant gene expression by a mechanism involving type 2 cGMP-dependent protein kinase that renders the intestinal epithelium more resistant to redox stress (Am J Pathol. 2017 Feb;187(2):377-389. Epub 2016 Dec 18). The laboratory has also shown that increasing cGMP, using either sildenafil or the guanylyl-cyclase C agonist, linaclotide, is therapeutic for constipation and can prevent colon cancer in preclinical models (Gastroenterology. 2016, 150(4):S625, S697).

Han-Fei Ding, PhD

The Ding laboratory studies the molecular and cellular bases of cancer development in model systems. It is well established that cancer cells reprogram their metabolism to meet the biosynthetic challenge of growth and proliferation. How cancer metabolism is initiated and maintained in cancer cells is a central question of cancer research. A major research area of the Ding laboratory is to investigate the role of histone methylation states in the transcriptional regulation of cancer metabolism. The histone lysine demethylase KDM4C is often overexpressed in cancers, primarily through gene amplification. The molecular mechanisms of KDM4C action in tumorigenesis are not well defined. In a study published in Cell Reports, Dr. Ding and colleagues reported that KDM4C transcriptionally activates amino acid biosynthesis and transport, leading to a significant increase in intracellular amino acid levels. Examination of the serine-glycine synthesis pathway revealed that KDM4C epigenetically activates the pathway genes under steady-state and serine deprivation conditions by removing the repressive histone modification H3 lysine 9 (H3K9) trimethylation. This action of KDM4C requires ATF4, a transcriptional master regulator of amino acid metabolism and stress responses. KDM4C activates ATF4 transcription and interacts with ATF4 to target serine pathway genes for transcriptional activation. In addition, the study presented evidence for KDM4C in transcriptional coordination of amino acid metabolism and cell proliferation. These findings suggest a molecular mechanism linking KDM4C-mediated H3K9 demethylation and ATF4-mediated transactivation in reprogramming amino acid metabolism for cancer cell proliferation (Cell Rep. 2016, 14:506-19).

In a recently published study, the Ding laboratory examined metabolic pathways that may drive or maintain high-risk neuroblastoma, one of the deadliest childhood cancers. Transcriptional profiling of neuroblastoma stem cells from tumors of TH-MYCN mice, an animal model of high-risk neuroblastoma, revealed that these tumor stem cells acquire a metabolic program characterized by transcriptional activation of the cholesterol and serine-glycine synthesis pathways, primarily as a result of increased expression of sterol regulatory element-binding factors and Atf4, respectively. This metabolic reprogramming is recapitulated in high-risk human neuroblastomas and is prognostic for poor clinical outcome. Treating the mouse neuroblastoma stem cells and human neuroblastoma cell lines with statins, which inhibit the cholesterol synthesis pathway, reduced cell growth and tumorigenicity, as did shRNA-mediated knockdown of the enzyme PHGDH in the serine-glycine synthesis pathway. These findings suggest a therapeutic strategy for targeting the metabolic program of high-risk neuroblastoma (Cell Rep. 2016, 17:609-23).

Tumor Signaling & Angiogenesis

Georgia Cancer Coalition Distinguished Scholar Professor

In addition, Dr. Ding has collaborated with Dr. Hongjuan Cui at Southwest University of China to study the oncogenic function of HOXC9 in glioblastoma (Neuro Oncol. 2016, 18:819- 29) and the therapeutic potential of the antibiotic drug tigecycline in neuroblastoma (Tumour Biol. 2016, 37:7615-23).

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Ellen LeMosy, MD, PhD

Tumor Signaling & Angiogenesis

Associate Professor

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A long-standing interest of the LeMosy laboratory is in how proteins and carbohydrates within the extracellular matrix (ECM) microenvironment regulate growth factor signals transmitted between cells. One family of such growth factors is Wnts, present at high levels in some tumor microenvironments and showing aberrant intracellular signaling in many cancers. The Wnts also play critical roles in normal embryonic development, and a major concept in cancer biology is that developmental processes such as Wnt signaling and epithelial-to-mesenchymal transitions are re-used in the progression of cancer.

The LeMosy laboratory is currently studying Tinagl1, or tubulo-interstitial nephritis antigen-like protein, an ECM protein found in basement membranes of vasculature, epithelia, and smooth muscle. Tinagl1 has been postulated to have a role as a metastasis inhibitor in mouse and human breast cancer, but very little is known about its molecular interactions and thus how it might function. One physical interaction that has been identified is binding to secreted Wnts, where Tinagl1 has been postulated to be a positive cofactor.

Utilizing the zebrafish model to examine the normal functions of Tinagl1, the LeMosy laboratory demonstrated that Tinagl1 is required for craniofacial development, with defects in neural crest cells that form most of the bones of the face (Cleft Palate Craniofac J. 2016, PMID: 27243669). Neural crest cells undergo proliferation, an epithelial-to-mesenchymal transition, and long-distance migration before differentiating into cartilage within the pharyngeal arches, reminiscent of several events that occur in carcinoma metastasis. This project also demonstrated an apparent genetic interaction between reduction of Tinagl1 and Wnt3a, providing the first in vivo evidence supporting a role for Tinagl1 in Wnt signaling.

Work in the zebrafish system that provides additional insight into possible general mechanisms of Tinagl1 action has been presented at The Allied Genetics Conference (Orlando, July 2016) and is in preparation for publication in 2017. Extension of the project to mouse cell culture models, including cancer models, is underway to facilitate rapid study of the signaling pathways and cellular behaviors regulated

by Tinagl1.

Nita Maihle, PhD

Dr. Maihle’s laboratory has been a leader in the study of biologically targeted cancer therapeutics targeting the EGF/HER family of receptor tyrosine kinases for over two decades. Their studies were the first to demonstrate the mechanism of ligand-independent oncogenic signaling by EGFR, the first to demonstrate the mechanism of acquired resistance to the breast cancer drug trastuzumab (anti-HER2), and the first to demonstrate that alternate isoforms of human EGFR and HER3, as well as the interleukin 6 receptor (IL-6R), are generated through alternate transcription/splicing. These receptor isoforms have since been identified as the major circulating forms of these receptors in human blood, where they have shown early detection/diagnostic activity in cancers such as ovarian cancer and multiple myeloma. In recent years, Dr. Maihle and her colleagues have demonstrated the utility of HER-targeted therapies in the treatment of aggressive forms of endometrial cancer. During the past year, these studies resulted in identification of the drug metformin (used in type 2 diabetes patients) as a possible chemo-protective agent in endometrial cancer patients. Surprisingly, the basis for the protection observed with this drug appears to be epigenetic in both breast and endometrial cancer patients, and involves genome-wide changes in DNA methylation (Oncogene. 2016, doi: 10.1038/onc.2016.391). While these studies in endometrial cancer suggest the tumor cells themselves serve as the drug target, growing evidence suggests that breast tumor stromal cells may play an active role in both the etiology and progression of breast cancer (Am J Pathology. 2016, 186(5):1340-50). Emerging evidence suggests that tumor stromal cells and cells of the tumor vasculature (pericytes) may be inter-convertible – a process referred to as vascular mimicry. It is proposed that this process may provide one potential mechanism for the ‘leakiness’ observed in malignant breast tumors. Dr. Maihle is also involved in promoting diversity in the biomedical research workforce (Ethn Dis. 2016, 26(3):379-386).

Tumor Signaling & Angiogenesis

Georgia Cancer Center Associate Director, Education Professor

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Betty Pace, MD

Tumor Signaling & Angiogenesis

Professor

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For over two decades the Pace laboratory has conducted research to develop strategies to induce fetal hemoglobin expression to block sickle hemoglobin polymerization and improve the clinical symptoms of sickle cell disease (SCD). Recent multi-pronged approaches to define molecular mechanisms of gamma globin gene silencing during erythroid maturation has included microRNA analysis and a genome-wide association study. Using a combined in silico analysis and functional studies in human erythroid progenitors, the Pace laboratory demonstrated the ability of miR-34a to activate gamma globin through silencing the known repressor transcription factor STAT3 (Exp Biol Med. 2016, 241:719-29). The effects of the STAT3 mimic as a therapeutic strategy is under investigation. Dr. Pace also participated in collaborative research to discover the ability of synthetic zinc finger DNA-binding domains to activate gamma globin expression in human erythroid progenitors as an approach for gene therapy of SCD and Cooley’s anemia (Mol Ther Nucleic Acids. 2016, 5:e378). Furthermore, to expand the field on experimental and therapeutic approaches, Dr. Pace served as Guest Editor for a Special Edition on Sickle Cell Disease Severity in Experimental Biology Medicine (Maywood), April 2016. The Pace group discovered inherited genetic modifiers of gamma globin gene expression by conducting a genome-wide association study of DNA samples isolated from sickle cell patients followed in the Cooperative Study of Sickle Cell Disease (Exp Biol Med. 2016, 241:706-18). They confirmed the role of BCL11A as a gamma globin silencer and identified that novel proteins, including SPARC and Gfi1, correlated with levels of fetal hemoglobin in people with SCD. Experimental data are being collected to determine the functional role of these proteins in hemoglobin regulation during erythropoiesis. Dr. Pace has ongoing collaborations to develop combined DNA, RNA and protein multi-omic analysis to define regulatory networks associated with clinical severity in SCD (Exp Biol Med. 2016, 241:772-81). Along with her basic research program, Dr. Pace also is heavily involved in mentoring and training young investigators. She provides leadership for two NIH-funded training programs. Her trainee published data demonstrating the role of sickle hemoglobin in pulmonary endothelium cell dysfunction in sickle cell mice and the ability of beta-nicotinamide adenine dinucleotide to reverse the negative effects of sickle hemoglobin and improve barrier function to ameliorate pulmonary edema (Haematol. 2016, PMID: 27686374). The Pace laboratory also participated in collaborative work to identify the role of cathepsin K in endothelial cell function through the AP-1 and NFκB signaling pathways (Biol Chem. 2016, 397(5):459-68). Dr. Pace was awarded competitive renewal of the National Heart Lung and Blood R25 grant to establish a Program to Increase Diversity in Health-Related Research (PRIDE) in functional and translational genomics. To date, 75 underrepresented junior faculty members from institutions across the United States have been trained in the PRIDE program under her leadership.

An overview of the program and the impact on the success of trainees across the seven programs currently funded was published recently (Ethn Dis. 2016, 26:379).

Muthusamy Thangaraju, PhD

A main area of research focus in the Thangaraju laboratory is to understand the functional role of epigenetics, especially DNA methylation and histone modification, in the regulation of mammary stem and progenitor cells (MaSCs) and of breast cancer stem cells (BCSCs). The laboratory has recently shown that DNA methyltransferases (DNMTs), especially DNA methyltransferase 1 (DNMT1), play a critical role in mammary stem cell formation and maintenance. Mammary gland-specific DNMT1 deletion is associated with reduced MaSC formation, providing evidence that DNMT1 is indispensable for MaSC formation and maintenance. Evidence that DNMT1 deletion is associated with reduced mammary tumor formation by depleting cancer stem cells has also been determined. Further, pharmacological inactivation of DNMTs showed a significant reduction in mammary tumor formation and metastasis and that this reduced tumor incidence is associated with reduced BCSC formation and maintenance (Cancer Res. 2016, 76: 32243235). This study provides strong evidence that the combination of DNMT and histone deacetylase (HDAC) inhibitors drastically reduced mammary tumor formation. RNA-seq analysis using MaSCs and BCSCs that are treated with DNMT and HDAC inhibitors identified several genes that are differentially regulated between normal and breast cancer. These studies provide the pre-clinical evidence that BCSCs are intrinsically sensitive to epigenetic modifications and can therefore be significantly affected by epigenetic-based therapies, warranting a detailed investigation of combined DNMT and HDAC inhibition in refractory or drug-resistant breast cancer.

Tumor Signaling & Angiogenesis

Associate Professor

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Guangyu Wu, PhD

Tumor Signaling & Angiogenesis

Professor

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The Wu laboratory is interested in dissecting the molecular mechanisms underlying the intracellular trafficking of G protein-coupled receptors (GPCRs), particularly the processes that control the receptors’ transport from the endoplasmic reticulum (ER), where they are made, to their functional destination at the cell surface. Their recent studies have identified GGAs (Golgi-localized, γ-adaptin ear domain homology, ADP ribosylation factor-binding proteins), a family of multidomain clathrin adaptor proteins that sort cargo proteins at the trans-Golgi network to the endosome/lysosome pathway, as important regulators in GPCR transport from the Golgi. Interestingly, three GGA proteins all directly interact with the receptor but via distinct domains (Mol Cell Biol. 2016, 36:1152; Sci Rep. 2016, 6:37921).

They are also interested in studying the roles of GPCRs and G proteins in cancer biology. They have demonstrated that the small G protein ADP-ribosylation factor 1 (ARF1), which has been well defined as an important regulator in vesicle-mediated membrane trafficking, plays a crucial role in the activation of the oncogenic MAPK ERK1/2 pathway in prostate cancer as well as prostate tumorigenesis. These data suggest that ARF1 is a key molecular target for prostate cancer therapeutics and diagnosis (Oncotarget.

2016, 7:39834). In addition, in collaboration with Dr. Yong Teng (Georgia Cancer Center), the Wu laboratory has shown that inhibiting ARF1 activation may represent a potential therapeutic approach to prevent or treat breast cancer metastasis (Oncotarget. 2016, 7:58111).

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Cancer Prevention & Control

Cancer Prevention & Control

OVERVIEW

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The Georgia Cancer Center is building a focus in cancer prevention through the Cancer Prevention & Control (CPC) Program. A major theme is to bring cancer prevention efforts to medically underserved regions of the state of Georgia that show significant disparity in outcomes in minority populations. Current efforts involve the relationship between HPV and cervical cancer, supported by clinical research centers in Georgia and in rural districts of Peru where there is a significantly increased incidence of cervical cancer. In this area, the focus is on diagnostics and prevention as well as behavioral research associated with screening. These studies are also extended to epidemiology studies about uptake of HPV vaccination in rural Georgia.

Lung cancer is the number one cause of cancer death and is prevalent in Georgia. Fortunately, early detection with low-dose CT scans can save lives. To address this issue, the Georgia Cancer Center has developed a lung cancer screening program that is offered at no charge. Encouraging results have been obtained so far in a relatively large cohort of volunteers. As part of this overall effort, the Georgia Cancer Center serves as the hub of a smoking cessation program designed to offer counseling and behavioral intervention to reduce smoking. This effort promotes tobacco cessation in parents and preventing initiation of tobacco use in children, as well as underage alcohol abuse and use of e-cigarettes in underserved rural areas of Georgia. To reduce cancer morbidity and mortality in Georgia, the Georgia Cancer Center, supported by the Bristol-Myers Squibb Foundation, launched the cancer-Community Awareness Research Access and Education (c-CARE) initiative. The overall aim of c-CARE is to improve cancer outcomes among minority and medically underserved communities. The four-part c-CARE initiative includes: (1) cancer awareness campaigns through outreach and social media; (2) population-based assessment of screening prevalence and cancer risk behaviors; (3) educational sessions offered by community health workers within churches, clinics and community recreation centers; and (4) navigation to free lung cancer screening and tobacco cessation services.

Additional studies are using complex population and patient databases to investigate risk factors and potential biomarkers for breast and colorectal cancer incidence and outcomes.

CPC Program Members Laboratory Focus

Candace Best, PhD

Increasing human papillomavirus (HPV) vaccine uptake in Georgia

Daron G. Ferris, MD

The prevention, screening, diagnosis, and treatment of human papillomavirus (HPV)-induced cancers, primarily those of the anogenital tract

Sharad Ghamande, MD

Increase awareness of and participation in NCI-sponsored clinical trials and cancer care delivery research throughout Georgia, particularly among minority and underserved populations

Sangmi Kim, PhD

Population-based and clinical studies related to biomarkers and modifiable lifestyle factors to refine cancer prevention strategies, maximizing the benefits of interventions and minimizing unnecessary harms and costs

Carsten Schroeder, MD

The free low-dose CT lung screening program

Michael E. Stefanek, PhD

Issues related to decision making and risk perception in health

Martha S. Tingen, PhD, MSN

Primary and secondary prevention of the usage of tobacco, a substance of abuse that contributes to 30 cancers and is the primary cause of lung cancer

Lovoria B. Williams, PhD, APRN-BC

Cancer-Community Awareness Research Access and Education (c-CARE) initiative to improve cancer outcomes among minority and medically underserved communities

Cancer Prevention & Control

CPC Program Member

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Candace Best, PhD Assistant Professor

Cancer Prevention & Control

The Best laboratory is focused on Cancer Prevention and Control through the investigation of human papillomavirus (HPV). Specifically, Dr. Best and colleagues have focused on increasing HPV vaccine uptake in Georgia, where HPV vaccine uptake remains low and HPV infection, disease, and related cancers continue to have an enormous burden in peoples’ lives. Moreover, current intervention strategies to improve HPV vaccine uptake have been less than effective for reasons that remain unanswered by the scientific literature.

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The Best research strategy is to utilize a systematic mixed-method approach to improve HPV vaccine uptake. Considerable time and effort has been taken to identify health care providers (HCPs) in Georgia who are engaging in both high and low levels of HPV vaccination. Georgia is one of a few states that collect and store county-level vaccination records in a centralized database. Dr. Best has been coordinating with the Department of Biostatistics and Epidemiology at Augusta University to finish cleaning and analyzing this data to identify counties with high and low levels of HPV vaccination. These data will then be mapped onto an HCP database of HCPs who are currently licensed and frequently administer the HPV vaccine (e.g., pediatricians) in those specific counties.

While data analyses are ongoing, Dr. Best has utilized opportunities to present preliminary data with her research team. In 2016, Dr. Best presented at Augusta University’s Celebration in Research & Creative Activities, the Southeastern Psychological Association, and the Society for Adolescent Health and Medicine. Of note, this work also supported four graduate and undergraduate student projects for the Augusta University Summer Scholars Program and the Fall 2016 Center for Undergraduate Research and Scholarship Brown Bag Presentation. This also led to obtaining other grants to further support this project.

Overall, this research will provide the platform for future qualitative studies to investigate meaningful characteristics of HCPs who engage in different HPV vaccination practices across the state.

Daron G. Ferris, MD Director, HPV Epidemiology & Prevention Program Professor

Working with Dr. Juan Luque (Medical University of South Carolina), Dr. Ferris and colleagues examined a novel patient educational intervention in minority women living in rural Georgia. They examined the feasibility and efficacy of Salud es Vida (Health is Life), a promotora-led, Spanish language educational group session on cervical cancer screening (Pap tests), self-efficacy (belief in ability to schedule and complete a Pap test), and knowledge. The study participants were immigrant Hispanic/Latina women from farmworker backgrounds, a population that has significantly higher cervical cancer mortality rates than non-Hispanic whites. The two-arm, quasi-experimental study was conducted in Southeast Georgia in 2014-2015. Hispanic/Latina immigrant women aged 21-65 years and overdue for a Pap test were included as intervention (n = 38) and control (n = 52) group participants. The intervention group scored significantly higher on both cervical cancer knowledge recall and retention than the control group (p < 0.001).

The group intervention approach was associated with increased cervical cancer knowledge but not uptake of Pap test (J Cancer Educ. 2016, doi:10.1007/s13187-015-0978-x).

Dr. Ferris and colleagues also determined patients’ knowledge and attitudes concerning cervical cancer and HPV and the potential impact of a novel rural cervical cancer screening program. Peru is characterized by high cervical cancer incidence and mortality rates and by significant gaps in quality cervical cancer screening for the population. This descriptive, mixed methods study aimed to assess the attitudes and perceptions of medical staff, health care workers, and patients toward a cervical cancer screening program that included both clinic-based and community outreach services conducted by the nongovernmental clinic, CerviCusco. The study also explored patient knowledge and attitudes around cervical cancer and about HPV to inform patient education efforts. Participants liked that the services were free and of good quality. CerviCusco has demonstrated its capacity to provide screening outreach campaigns to populations who had not previously had access to liquid-based cytology services. The finding that patients had generally low levels of knowledge about cervical cancer and the HPV vaccine prompted the development of culturally and linguistically appropriate educational and promotional materials to improve the educational component of the periodic campaigns conducted primarily in rural areas of Andean Peru (Patient Prefer Adherence. 2016, 10:2107-2116).

Cancer Prevention & Control

Dr. Daron Ferris’s research focuses on the prevention, screening, diagnosis, and treatment of human papillomavirus (HPV)-induced cancers, primarily those of the anogenital tract. His clinical trials are conducted in both the US and at his clinical research center, CerviCusco (www.cervicusco.org), in Peru.

Dr. Ferris and his research team also conducted a social network study to examine cervical cancer screening history and social network characteristics in a rural indigenous community that participated in CerviCusco’s screening campaigns in 2012 and 2013. Bivariate results found significant differences in percentage of alter composition for neighbors and family, and for mean number of years known, mean density, and mean degree centrality between women who had received a Pap test (n = 19) compared to those who had not (n = 50) (p < 0.05). The final logistic regression model was statistically significant (χ2 (2) = 20.911, p < .001) and included the variables for percentage of family alter composition and mean density, and it explained 37.8% (Nagelkerke R(2)) of the variance in Pap test receipt, correctly classifying 78.3% of cases. According to this exploratory study, female neighbors versus family members may have provided an important source of social support for healthcare decisions related to receipt of a Pap test (BMC Public Health. 2016, 16:181).

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Sharad Ghamande, MD Georgia Cancer Center Associate Director, Clinical Affairs Professor

Cancer Prevention & Control

Dr. Sharad Ghamande, Associate Director of Clinical Research for the Georgia Cancer Center, is principal investigator for a five-year grant to support a National Cancer Institute (NCI) Community Oncology Research Program Minority/Underserved Community Site (NCORP M/U). Known locally as GA CaRes (Georgia Cancer Research), the program is a partnership between the Georgia Cancer Center, the Morehouse School of Medicine (Atlanta), University Cancer and Blood Center (Athens), and the Jiann-Ping Hsu College of Public Health at Georgia Southern University (Statesboro) to increase awareness of and participation in NCI-sponsored clinical trials and cancer care delivery research throughout Georgia, particularly among minority and underserved populations.

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The NCORP replaced both the NCI Community Clinical Oncology Program (CCOP) and the NCI Community Cancer Centers Program (NCCP) and is an essential component of NCIâ&#x20AC;&#x2122;s National Clinical Trials Network.

As the only NCORP Minority/Underserved Community Site for Georgia, and one of just 12 selected nationally, the Georgia Cancer Centerâ&#x20AC;&#x201C;led consortium contributes to the design and translation of the national NCORP research agenda, particularly for studies pertaining to minority and underserved populations. Key stakeholders and community partners are engaged to learn their priorities for communitybased cancer research and to work collectively to address the historic barriers that have stood in the way of minority and underserved patients participating in clinical trials and other important cancer research. NCORP helps the Georgia Cancer Center to positively impact the tremendous cancer health disparities that exist in Georgia among minorities and medically underserved populations.

Currently, Augusta University has 35 adult and 18 pediatric clinical trials open. The Athens group has 27 open adult clinical trials, and the additional affiliate sites, DeKalb Medical Center in Decatur and Phoebe Putney Memorial Hospital in Albany, have 29 and 9 open adult trials, respectively.

An exciting new initiative for GA CaRes is participation in the NCI-MATCH (Molecular Analysis for Therapy Choice) Trial, which analyzes patient tumors for specific gene abnormalities for which a targeted drug exists. The objective of the trial is to determine the effectiveness of treating cancers according to their molecular abnormalities. GA CaRes has screened 43 patients since June 2016, of which 4 have matched to a treatment trial.

Sangmi Kim, PhD

Dr. Kim conducts clinical and population health studies using complex population and patient databases from different sources including patient surveys, retrospective chart reviews and electronic medical records, cancer registries, and population-based epidemiological studies. Her major areas of research have been molecular and biochemical biomarkers and modifiable lifestyle factors, including those mediating inflammation. Biomarkers that accurately and reproducibly reflect biological mechanisms underlying diseases and interventions are an important tool for exploiting the rapidly-increasing molecular understanding of disease processes for clinical application. Specifically, in a cancer prevention setting, effective biomarkers can refine cancer prevention strategies towards precision prevention that maximizes the benefits of interventions while minimizing unnecessary harms and costs. In this regard, Dr. Kimâ&#x20AC;&#x2122;s recent projects have focused on investigating the utility of urinary levels of the prostaglandin E 2 metabolite (PGE-M) to improve aspirin-based chemoprevention strategies. Urinary PGE-M levels serve as a reliable indicator of systemic production of PGE2, a therapeutic target of NSAIDs, and thus may represent a promising biomarker that can predict PGE2 -mediated breast cancer risk. In collaboration with colleagues at NIEHS, Dr. Kim previously reported that high urinary PGE-M levels were associated with an increased breast cancer risk among postmenopausal women who did not regularly use NSAIDs. Because PGE 2 also stimulates aromatase activation to promote estrogen biosynthesis in mammary adipose tissues, her recent work determined urinary estrogen levels among these women to investigate the relationship of urinary PGE-M, urinary estrogen levels, and breast cancer risk. The analysis shows that urinary PGE-M levels were only modestly correlated with urinary levels of estrone and estradiol, and additional adjustment for urinary PGE-M made only a nominal change in the hazard ratios (HRs) for the association between urinary levels of parent estrogens and breast cancer risk. Similarly, the association between urinary PGE-M levels and breast cancer risk persisted after additional adjustment for urinary levels of parent estrogens. The data suggest that the increased risk associated with urinary PGE-M levels might not be fully explained by the estrogen-breast cancer association alone but also by additional effects related to inflammation, and that the chemopreventive potential of NSAIDs may not be particularly greater for estrogen receptor positive (ER+) or postmenopausal breast cancer (Cancer Epidemiol Biomarkers Prev.

2016, PMID: 27864342).

Another line of Dr. Kimâ&#x20AC;&#x2122;s research is to investigate a role of inflammation and immune modulation in cancer outcomes and survivorship. The pretreatment neutrophil:lymphocyte ratio (NLR), derived from differential white blood cell (WBC) counts, is a parameter of systemic inflammation and host immune reaction, which is routinely available in the clinical setting. In a retrospective chart review of breast cancer patients at Georgia Cancer Center, Dr. Kimâ&#x20AC;&#x2122;s group found that elevation in pretreatment NLR was an independent predictor of overall survival among nonmetastatic breast cancer patients. The data suggest that combined with other markers of local and systemic inflammation, NLR, a low-cost, reliable marker of inflammation, may have potential utility in predicting short- and long-term prognosis and risk stratification for anti-inflammatory or immune therapy for cancer patients in the future (Front Oncol. 2016, 6:81). Along this line of research, Dr. Kim is also collaborating with Drs. David Munn and Theodore Johnson (Georgia Cancer Center) to develop a research study to compare radiation-related symptoms and quality of life in pediatric brain cancer patients treated with indoximod versus other therapeutic options.

Cancer Prevention & Control

Assistant Professor

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Carsten Schroeder, MD Director, Cancer Center Thoracic Oncology Surgery Service Associate Professor

Cancer Prevention & Control

The National Lung Screening Trial (NLST) reported lung cancer in 1% of high-risk persons and demonstrated that screening high-risk individuals with low-dose CT (LDCT) of the chest saves lives. To increase screening accessibility in its underserved catchment area, the Georgia Cancer Center developed a free LDCT lung screening program for individuals meeting the National Comprehensive Cancer Network (NCCN) high-risk criteria.

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The program, led by Carsten Schroeder, MD, enrolled 398 people in its first year; 355 participants qualified and 272 were screened. Eight participants (2.9%) had lung cancer, six of whom had the disease detected in early stages. Fifty percent of the participants screened were current smokers and did not admit symptoms at the time of screening. After adjusting for patients symptomatic on clinical evaluation, the program reported an occurrence of cancer at 2.2% versus 1.1% nationally. Looking at disparity data in the screening population, an even higher rate of lung cancers was found in high-risk African Americans (up to 5%, including symptomatic). Screening and finding lung cancers in earlier stages will significantly improve patient survival.

The study has been presented as a podium presentation at the Society of Thoracic Surgeons Annual Conference in Phoenix, AZ in January 2016 (South Med J. 2017,110(3):188-194).

Martha S. Tingen, PhD, MSN

Dr. Martha S. Tingen, Director of Tobacco Control for the Georgia Cancer Center, focuses on primary and secondary prevention of tobacco use, a substance of abuse that contributes to 30 cancers and is the primary cause of lung cancer. Her team’s work also addresses health disparities with populations that suffer disproportionately worse outcomes at every area along the cancer continuum. Whether due to a lack of available services from being under-insured or not insured, a late diagnosis often contributes to more adverse medical and surgical outcomes or lack of understanding of proper self-care, and the resultant cancer health care disparities are extensive in our communities, region, and nation-wide. Clinical trials and outreach services and programs are conducted in our communities and regions most particularly affected by cancer health disparities.

A primary focus of Dr. Tingen’s work is on promoting tobacco cessation in parents and preventing both the initiation of tobacco and electronic cigarette (e-cigarette) usage in children and underage alcohol abuse through efforts sponsored by the State of Georgia. Working with Dr. Lovoria Williams (Georgia Cancer Center) and supported by Bristol-Myers Squibb Foundation, the cancer-Community Awareness Access Research & Education (c-CARE) project focuses on underserved areas and involves community agencies. The goals of the project are to provide education on the health risks for lung cancer, free screening for those eligible for low-dose CT to detect early lung nodules, and state-of-the-art free tobacco cessation for smokers. Baseline and sociodemographic assessments were obtained on cancer risks and screening behaviors among all participants (N=376) to include breast cancer, cervical cancer, lung cancer, colorectal cancer, and skin care. Dr. Tingen also collaborates with Dr. Vahe Heboyan in Augusta University’s College of Allied Heath with interest in prevention of e-cigarette usage. This project is exploring the effectiveness of increasing knowledge of e-cigarettes based on an intervention that is webbased, interactive, and educational. This is currently being tested with 6th-8th graders in a disparate area of our community. Dr. Tingen’s research with Dr. Catherine Davis (Augusta University) explored the impact of passive smoke exposure in overweight and obese children and found substantial differences in cognition scores (worse for those exposed versus non-exposed peers), and those exposed also had greater central adiposity than those not exposed. Dr. Tingen also serves as the Cancer Care Delivery Research (CCDR) Lead for the NCORP M/U NCI award (Dr. S. Ghamande, PI). In the fall of 2016, Dr. Tingen was appointed to the CCDR Coordinating Committee for the National Cancer Institute’s Community Oncology Research Program.

Cancer Prevention & Control

Director, Tobacco Control Associate Professor

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Lovoria B. Williams, PhD, APRN-BC

Cancer Prevention & Control

Associate Professor

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Dr. Lovoria Williams leads the Georgia Cancer Centerâ&#x20AC;&#x2122;s cancer-Community Awareness Research Access and Education (c-CARE) initiative. The overall aim of c-CARE is to improve cancer outcomes among minority and medically underserved communities. The four-part c-CARE initiative includes: (1) cancer awareness campaigns through outreach and social media; (2) population-based assessment of screening prevalence and cancer risk behaviors; (3) educational sessions offered by Community Health Workers within community settings; and (4) navigation to cancer screening and services. To date, 12 community sites are enrolled: seven African-American churches, four federally qualified clinics, and one community recreation center. Researchers will train four Community Health Workers from within each community site to deliver four 90-minute long education sessions and to recruit 50 English-speaking adults aged 2180 years. High-risk individuals will be connected to lung cancer screening opportunities and tobacco cessation programs. Pre- and post-intervention outcome measures will be collected with surveys to assess changes in participant knowledge, attitudes and beliefs regarding cancer, perceived barriers and selfefficacy to obtain lung cancer screening. A site-level survey will be conducted at each site during project Year 1 to obtain a baseline measure of the populationâ&#x20AC;&#x2122;s cancer screening and prevention behaviors preintervention; the site-level survey will be repeated in Year 3 to measure the impact of the intervention on the same measures.

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Georgia Cancer Center Community Outreach

Georgia Cancer Center Community Outreach

http://www.augusta.edu/cancer/community/

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OVERVIEW The Office of Cancer Information and Awareness (OCIA) provides customer serviceoriented community outreach, engagement, and education for a range of community and university partners and individuals with varying literacy levels using a variety of multi-media formats. In 2016, through presentations, educational announcements, and direct one-to-one contact, the office engaged 5,797 people, attended 130 events, and furnished an additional 21 events with approximately 3,300 educational materials.

Services include giving presentations on a variety of cancer topics as well Christine O’Meara, MA, MPH as on the Georgia Cancer Center’s role in the community to churches; Director, Office of Cancer Incivic organizations; health and social service organizations; professional formation and Awareness associations; government agencies (e.g., Columbia County Human Resources, Augusta-Richmond County Public Library, Augusta-Richmond County Safety Officers); K-12 public and private schools; and Augusta University (AU) undergraduate and professional degree programs.

The OCIA maintains an ongoing partnership with the Georgia Prevention Institute to provide tobacco and electronic-cigarette educational sessions to the community, AU undergraduates, AU employees, and Dental College of Georgia and Medical College of Georgia students, faculty, residents, and fellows. New in 2016 is the Potash “Your Health Matters Series,” a four-part interactive educational series addressing Breast Cancer, Obesity and the Link with Cancer, Skin Cancer, and Tobacco/Electronic-Cigarettes provided to seniors at a community center and elementary school children at an after-school sports academy.

A train-the-trainer program, Student Cancer Out-Reach & Education (SCORE), was initiated with AU Health System’s Sports Medicine’s Athletic Trainers housed in three South Carolina high schools.

Educational Exhibits. Community engagement occurs at community clinics and at health fairs and events in Richmond, Columbia, Burke, McDuffie and Aiken counties, including those sponsored by AugustaRichmond County Department of Recreation and Parks and McDuffie County Cooperative Extension Service.

The OCIA seizes opportunities to inform the community about cancer in non-traditional venues such as the Augusta-Richmond County Earth Day Event in April, the 4 th of July city-wide celebration, and the November Stand Down for Homelessness with a focus on skin cancer prevention. Providing cancer-related educational exhibits or displays at urban and rural churches, community health fairs, the Greater Augusta Healthcare Network (GAHN) partners including community clinics, and AU new student orientation and the employee benefits fair continued throughout the year. Participation at the AU College of Nursing’s Costa-Layman Health Fair for rural South Carolina farm workers constitutes our largest Latino outreach initiative where a Spanish language interpreter helps inform about skin cancer prevention, tobacco cessation, and colorectal cancer screening.

Community Health Needs Assessment. To ensure that the Georgia Cancer Center meets the Commission on Cancer Accreditation Standard 3.1 Patient Navigation Process “A patient navigation process, driven by a community needs assessment is established to address health care disparities and barriers to care for patients,” and to inform the OCIA’s educational, outreach, and research initiatives, the Office undertook a community health needs assessment (CHNA). An on-line, cancer-related survey was developed and disseminated to a random sample of AU students and employees and distributed to community groups and partners who, in turn, dispersed the survey to their constituencies. An additional 25 inperson surveys were administered for a total of 420 completed surveys. Four focus groups were conducted (N=25 participants from the Cancer Care Ministry at Good Shepherd Missionary Baptist Church, the Concerned Black Nurses Association, the AU College of Nursing Community Advisory Board, and Georgia Cancer Center patient advisors), and 10 key informant interviews were completed with community and public health leaders, a cancer survivor, and a community health clinic referral staff. CHNA results were shared at the Cancer Committee’s quarterly meeting on November 15. Upon completion of the primary and secondary data analyses, results will inform community and patient navigation initiatives to be implemented in 2017.

The OCIA managed a second successful annual Pink Pumpkin Party for breast cancer awareness, the Cancer Center’s signature breast cancer community event, held October 1, 2016. The seasonal festive and fun community event engaged about 250 individuals including families, cancer survivors, and cancer caregivers in a pumpkin-decorating competition, raising funds to provide 10-11 free 3-D mammograms at the AU Health Breast Health Center for women in need.

Multi-Media Educational Tools. Several multi-media educational tools were developed, added to the community education tool box, and disseminated. During the fourth quarter of our second year producing The C Word, our monthly electronic news brief featuring national cancer awareness topics, we distributed to 91 entities: churches (49), organizations/agencies (26), and individuals (16) throughout our regional Central Savannah River District (CSRA).

Churches, businesses, and organizations/agencies, in turn, disseminated the publication to their congregations, employees or members resulting in a potential annual circulation of 143,579. Three breast cancer survivor videos and the 2016 Pink Pumpkin Party video were produced and featured on the AU and Cancer Center’s websites. Two AU tobacco policy and cessation videos were updated and continue to be available through the institution’s website.

Participation in social media to inform the community about outreach activities was increased.

Georgia Cancer Center Community Outreach

Technical Assistance and Collaborations. Tobacco-Free/Smoke-Free Policy technical assistance was provided for the University System of Georgia’s Board of Regents, enabling the Georgia Cancer Center to be a key state-wide tobacco-related resource. Professional collaborations around community cancer prevention and screening/early detection education and promotion were cultivated with the American Cancer Society, the East Central Georgia Cancer Coalition, and the AU College of Nursing.

The integration of cancer topics into the undergraduate video production curriculum through collaboration with the AU Department of Communications continues to be a highlight. Maximizing a video production competition and social media component, students produced 24 Public Service Announcements about obesity and the link with cancer, resulting in seven award-winning PSAs and garnering over 1,200 audience favorite on-line votes through social media.

A newly developed brochure, Reality Check: Electronic-Cigarettes and Youth, provides up-to-date information about the composition of electronic cigarettes and their health consequences and promotes the Cancer Center’s cessation services. Over 8,000 educational materials were printed and distributed, including seven updated cancer-risk self-assessments produced by the OCIA.

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Georgia Cancer Center Education

Georgia Cancer Center Education

OVERVIEW

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The Georgia Cancer Center has advanced public, patient, and professional education and cancer-related training throughout the enterprise and in the community it serves in several important ways. Many of the public and patient education efforts are covered in the section on Community Outreach, through the Office of Cancer Information and Awareness. Working in conjunction with the OCIA, the Cancer Centerâ&#x20AC;&#x2122;s Office of Education assists in community education by providing content experts who have received training in communicating science to the public. These ambassadors, who include student trainees, research and clinical fellows, as well as staff and faculty, have a passion for sharing their knowledge with the Nita J. Maihle,PhD Georgia Cancer Center Associate next generation of scientists and physicians, while simultaneously Director, Education informing the community about the many exciting research projects and opportunities ongoing at the Georgia Cancer Center.

In addition to educating the public about recent and exciting developments in cancer research, the Office of Education has taken on the responsibility of updating physicians at the Medical College of Georgia, as well as in our community, in the fast-paced field of oncology clinical trials research. One aspect of our professional education programming has been provided through Augusta Universityâ&#x20AC;&#x2122;s Continuing Medical Education (CME)-accredited lecture series that brings in field leaders to share forefront knowledge with Cancer Center faculty as well as with community physicians. In addition, collaborative workshops and retreats have been hosted by the Georgia Cancer Center to support the exchange of professional ideas, to educate community physicians regarding recent advances in the field, and to foster collaborations with other regional entities (e.g., UGA and MUSC).

In addition to providing practicing physicians and scientists with the information needed to stay up-todate in their professions, the Cancer Center also strives to advance the field by training the next generation of physicians and scientists in oncology. The Cancer Center is an active participant in Augusta University training programs across the entire educational spectrum, from undergraduate and graduate programs (doctoral training) through residency and fellowship (postdoctoral training). In 2013 the Cancer Center initiated a new doctoral training program in Cancer Biology, in conjunction with the Department of Biochemistry & Molecular Biology. This new program has resulted in the development of new courses in Cancer Biology (undergraduate and graduate level), as well as new extracurricular programming to promote trainee career development. Peer mentorship among all trainees has been enhanced through the establishment of a new trainee-led Postdoctoral and Graduate Student Association (PGA), which works with Cancer Center leadership to foster the career development of all trainees. This programming includes monthly Professional Skills Development and Pathways to Success Workshops, which provide opportunities for trainees to develop their professional skills (statistical languages, communication, writing, and professional networking skills, among others), as well as to gain career perspectives and advice from successful biomedical professionals. In addition to these activities, three weekly Cancer Center seminar series, which separately feature ongoing research presentations by faculty, trainees, and invited (extramural) speakers, promote a sense of community within the Center, and also contribute to the development of both intramural and extramural collaborations. The trainee research seminar series further promotes trainee communication skills and culminates in a travel award competition. This competition is organized by the Cancer Center and sponsors travel support to allow the two top graduate students and the two top postdoctoral fellows to attend a national research meeting.

Near-term goals for the Cancer Center’s educational leadership include strengthening existing programs, as well as developing the curricula and experienced mentorship necessary to support the initiation of new professional fellowship training programs in fields such as Surgical Oncology, Radiation Oncology, Gynecology-Oncology, and Urologic Oncology. In addition, the Cancer Center plans to work closely with other colleges on the Health Sciences Campus to promote new initiatives in patient education, including enhanced community outreach initiatives.

Georgia Cancer Center Education

To support these professional education activities, the Cancer Center participates in a variety of national organizations and training consortia that exist to promote best practices in professional education in oncology and biomedical research. These include the Cancer Biology Training Consortium (CABTRAC), the NICHD-sponsored Women’s Reproductive Health Research Program Consortium (K12), the DODsponsored National Ovarian Cancer Academy, the Komen Foundation-sponsored Post-baccalaureate Training Program, and the ACGME-accredited Clinical Hematology/Oncology Fellowship training program. Through its programming, this fellowship training assists the Cancer Center’s clinical fellows in achieving the required ACGME core competencies and milestones. In addition to these national organizations, the Cancer Center has worked closely with the Saudi Arabian Cultural Mission (SACM) to provide new research training opportunities for clinicians planning to pursue careers in oncology; to date this program has graduated five SACM Scholars. This international program may be useful in the future as a model for the promotion of new global health initiatives and cancer-related training programs.

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Georgia Cancer Center Shared Resources

Georgia Cancer Center Shared Resources

OVERVIEW

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Lesleyann Hawthorn, PhD Director, Georgia Cancer Center Shared Resources Georgia Cancer Center Shared Resources provide access to technologies, services, and scientific consultation that enhance scientific interaction and productivity. The support of shared services for an entire center provides stability, reliability, cost-effectiveness, access to specialized technology and methodology, and quality control. The basic tenet of the shared facility archetype is to provide researchers with excellent services and facilities, and the scientific support staff to play a vital role in providing a focused environment within which researchers and clinicians can excel. The Georgia Cancer Center Shared Resources are in place to serve as an adjunct to the Shared Resources of the Medical College of Georgia and to assist researchers with development of protocols and technologies that would not be within the financial realm of the individual investigator.

Bioinformatics

Mission: To provide expertise in integrative computational-based analysis solutions to basic, clinical, and translational research applications. Bioinformatics is an interdisciplinary scientific field that develops methods for storing, retrieving, organizing and analyzing biological data, including the development of software tools to generate useful biological knowledge.

Analyses: Alternative Splicing: RNA De novo Genome Assembly: whole genome sequencing (WGS); RNA De novo Transcriptome Assembly: RNA Differential Enrichment: ChIP-seq for transcription factor (TF-ChIP); ChIP-seq for histone mark (HM-ChIP); Formaldehyde-assisted isolation of regulatory elements (FAIRE); DNase I hypersensitive sites sequencing (Dnase); Nucleosome positioning sequencing (Mnase) Differential Expression: RNA Differential Methylation: Whole genome bisulfite sequencing (WGBS); Reduced representation bisulfite sequencing (RRBS); Oxidative bisulfite sequencing (oxBS); Tet-assisted bisulfite sequencing (TAB); Nucleosome occupancy and methylome sequencing (NOMe); Infinium 45K Enrichment Identification: TF-ChIP; HM-ChIP; FAIRE; Dnase; Mnase Expression Profile: RNA Functional Annotation (GO, PPI, Pathway): All Gene Fusion: RNA Gene Set Enrichment Analysis: RNA Methylation Profile: WGBS; RRBS; oxBS; TAB; NOMe; Infinium 45K NCBI Deposit: All Quality Assessment: All Read Mapping: All Sequence Motif: TF-ChIP Sequence Variants: WGS; Whole exome sequencing (WES); Target sequencing (TS) Structure Variants: WGS

Georgia Cancer Center Shared Resources

Director: Sam Chang, PhD http://www.augusta.edu/cancer/research/shared/ bioinformatics/

Equipment: Georgia Cancer Center High Performance Computing Cluster (HPC): The HPC cluster consists of 2 Rack and 8 Blade servers with 36 AMD 12-core CPUs and 64GB RAM from HP Corporate running Linux, dedicated for computational research. This cluster includes a 2-way SMP system acting as front-end cluster nodes and a file server, a large memory 2-way SMP system acting as a web front-end and a database server. Storage with approximately 36TB of raw storage capacity is shared out to the computational nodes. All file systems are built on top of a parity RAID scheme using RedHatâ&#x20AC;&#x2122;s XFS. Image courtesy of David Castillo Dominici / FreeDigitalPhotos.net

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Biostatistics

Georgia Cancer Center Shared Resources

Director: Ramses Sadek, PhD http://www.augusta.edu/cancer/research/shared/ biostatistics/

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Mission: To provide collaborative support and education in all areas of biostatistics, including data mining (using local and national databases for hypotheses generation and scientific investigation) and study design, analysis, and interpretation, as well as interaction with industry, government, and regulatory agencies in the areas of clinical trials, epidemiology, and laboratory studies. This resource is available for efficient and accurate database design and management of clinical research data.

General Services and Activities  Consultation and quantitative research in collaboration with scientists across basic, population, and clinical sciences; engaged in the planning, conduct, and interpretation of research; address statistical needs related to protocol design, analysis and interpretation of clinical trials, in addition to interaction with sponsors and regulatory agencies. 

Statistical needs for non-intervention studies in basic and population sciences.

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Educational programs for research, clinical faculty, residents, and fellows.

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Assist in study design, statistical analysis, sample size and power considerations, and grant and manuscript preparation.

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Statistical programming in SAS, R, SPSS, STATA.

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Data mining of SEER, Augusta University registry, and national databases for hypotheses generation and answering scientific inquires by researchers.

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Serve in the Clinical Trials Protocol Review and Monitoring Committee (PRMC).

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Utilize and adapt novel statistical methodologies to respond to challenging cancer research issues.

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Collaborate with academia and government agencies such as CDC, Departments of Health, NIH, and university cancer centers and biostatistics departments.

Flow Cytometry

Mission: To provide high-quality, cost-effective, state-of-the-art flow cytometry and multiparameter cell-sorting instrumentation, expertise, and services. The facility maximizes the efficient utilization of the equipment, which affords the ability to perform almost every published flow cytometry protocol and serves to enhance the quality and scope of scientific research performed at the Cancer Center.

Equipment: The Georgia Cancer Center Flow Cytometry Core Facility is equipped with 6 flow cytometers that are categorized into 3 types: 

Three bench-top analyzer Becton Dickinson flow cytometers are typically operated by investigators themselves: a 2-laser FACSCanto, a 5-laser LSR II SORP, and a 4-laser LSR II SORP with highthroughput sampler (HTS).



A state-of-the-art imaging flow cytometer is typically operated by investigators themselves: The Amnis ImageStreamXdigital imaging flow cytometer [6 channels, 4 lasers], the first in the state of Georgia, provides a breakthrough in flow cytometry by providing imaging capability to flow cytometry (multispectral imaging flow cytometry) that can identify a single cell based on fluorescence dye intensity, morphology of the cell by bright field imaging, as well as morphology and distribution of fluorescence markers (reporters).



Two cell-sorting flow cytometers are provided as a service to investigators: 1) Becton Dickinson 4laser, 18-color FACSAria Special Order Research Products (SORP); 2) Becton Dickinson 4-laser, 18color influx.

In order to select the best fluorophores for use in a specific application on a particular flow cytometer, it is necessary to know the laser configuration of the cytometer and its optical configuration and detectors. The facility's lasers are summarized in the table posted at http://www.augusta.edu/cancer/ research/shared/flow/. Each cytometer's configuration is detailed in the section specific to the cytometer. The facility is able to accommodate the majority of flow cytometry protocols.

Georgia Cancer Center Shared Resources

Director: Ningchun Xu, PhD http://www.augusta.edu/cancer/research/shared/flow/

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Small Animal Imaging

Georgia Cancer Center Shared Resources

http://www.augusta.edu/cancer/ research/shared/smallanimal/

Ali Arbab, MBBS, PhD Scientific Director

The Small Animal Imaging Resource has been commissioned to provide a wide range of imaging and radiation treatment resources for animal research. The preclinical services are translational in operation while remaining cutting edge in the advancement of basic research. The services are available to the Augusta University research enterprise and other outside scientific investigators.

Instrumentation/Resources:



Magnetic Resonance Imaging (MRI) is performed on a Bruker Biospin 7T horizontal, 30 cm bore scanner. Two gradients are available to accommodate both small and large-sized rodents.

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Single Photon Emission Computed Tomography (SPECT) BioScan nanoSPECT/CT, a dual modality system for imaging mice, rats, and small rabbits. The system is capable of imaging a range of isotopes from the low energy of 125 I to 111 In, alone or in dual isotope acquisition mode. The Resource also has a license to use all clinically approved radiotracers for SPECT studies.

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Small Animal Radiation Research Platform (SAARP) provides image-guided micro-irradiation (IGMI) technology for radiobiology research purposes. It generates X-Ray doses up to 225kV with a range of 0-30mA and a maximum power limit of 3kW.

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Bioluminescence and Fluorescence Optical Imaging. Optical Images are created non-invasively via the detection of photons emitted by specific tracers. The cameras are able to detect wavelengths for 400-800 nm and from sources as little as 500 cells.

 

Infusion system and animal prep bench Image analysis software packages: ImageJ; Paravision; Matlab; Amira; MRIcro

Services Include:

       

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Ping-Chang Lin, PhD Director, MRI Physicist

Magnetic Resonance Imaging (MRI) Single Photon Emission Computed Tomography Bioluminescence Imaging Fluorescence Imaging X-Ray Imaging Radiation Therapy Image Data Analysis (simple and complex) Image Analysis Software Development

Biorepository

The Biorepository was established with support from the Georgia Cancer Coalition (GCC). This Biorepository is a state-wide resource; samples are collected from 6 participating sites across the state of Georgia (the Bio-Repository Alliance of Georgia for Oncology or BRAG-Onc) and represent the diversity of cancer patients in the state, enhancing cancer research in Georgia.

The Biorepository collects and stores specimens under standardized conditions with accompanying clinical and demographic information and appropriate patient consent, in compliance with the most current Best Practices for Biorepositories as recommended by NCIâ&#x20AC;&#x2122;s OBBR and ISBER. The repository collection includes a variety of specimen types, including tissue (tumor and matched adjacent normal), blood, and other biofluids, tumor cells, and specimens as needed.

All specimens are reviewed by a trained pathologist for quality assessment. Tissue specimens are fastfrozen in vapor phase liquid nitrogen to preserve their integrity and stored in large cryofreezers at -170 to -190°C. Blood is routinely separated into serum or plasma and buffy coats prior to freezing. Blood derivatives are stored at -70 to -80°C. The freezers are monitored constantly and are connected to an alarm system to ensure that the low temperatures are maintained.

Other methods of preparation and handling (such as fresh tissue or tumor cells for culture) are available by arrangement. A specialized Bone Marrow Repository for hematopoietic malignancies and disorders preserves frozen viable mononuclear cells, enriched by gradient centrifugation.

The repository is a critical bridge between the clinical and research endeavors in personalized medicine.

Georgia Cancer Center Shared Resources

Director: Roni Bollag, MD, PhD http://www.augusta.edu/cancer/research/shared/ tumor/

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Integrated Genomics

Georgia Cancer Center Shared Resources

Director: Eiko Kitamura, PhD http://www.augusta.edu/cancer/research/shared/ genomics/

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The Integrated Genomics Shared Resource houses a complete Illumina NextGen Sequencing Facility including both HiSeq and MiSeq instruments. Expertise for performing DNA-Seq, RNA-Seq, Chip-Seq, Methyl-Seq and targeted re-sequencing is available. Microarray resources include Affymetrix ® and Agilent ® Scanner Platforms that facilitate exon-specific, oligonucleotide and genome-wide arrays. Bioinformatics support is available for data analysis for both sequencing and microarray data.

Microarray Technology Equipment / Infrastructure

Next Generation Sequencing Equipment / Infrastructure

       

    

Agilent ® 2100 Bioanalyzer

  

Illumina Miseq



Pyrosequencer (Qiagen PyroMark MD / PyroMark Q96 workstation)



IlluminaCompute HPC analysis and storage system with 2 Rack and 8 Blade servers with 36 AMD 16-core CPUs and 64GB RAM from Dell Corporate running Linux, dedicated for computational analysis. This cluster includes a 2-way SMP system acting as front-end cluster nodes and a file server, a large memory 2-way SMP system acting as a web front-end and a database server. Storage with approximately 60TB of raw storage capacity is shared out to the computational nodes. All file systems are built on top of a parity RAID scheme using RedHat XFS.



Affymetrix ® GeneChip Scanner 3000 7G Plus Affymetrix ® Hybridization Oven 640 Affymetrix ® Fluidics Station 450 (x2) Agilent Microarray Scanner ®

Agilent ® Hybridization Oven for Array Slides Agilent ® 2100 Bioanalyzer Agilent ® 2200 TapeStation Applied Biosystems GeneAmp 9700 Thermocycler NanoDrop 1000

Agilent ® 2200 TapeStation NanoDrop 1000 QuBit Fluorometer Illumina HiSeq 2500 (Rapid & Hi-Throughput Modes) cBot Cluster Generation System Applied Biosystems GeneAmp 9700 Thermocycler

Proteomics and Metabolomics

The proteomics platform offers state-of-the-art proteomics services using the Thermo Scientific Orbitrap Velos Pro hybrid mass spectrometer that is interfaced to a Thermo Scientific Dionex UltiMate 3000 RSLC nano Ultra Performance Liquid Chromatography to provide robust, fast, ultra-sensitive, and high mass accuracy measurements for all classes of biomolecules. It boasts a resolving power that exceeds 100,000 and mass accuracy better than 1 ppm RMS. Additionally, it offers multiple fragmentation techniques, including Collision Induced Dissociation, Higher Collisional Energy Dissociation, and optionally Electron Transfer Dissociation, as well as parallel MS and MSn analysis.

The metabolomics platform consists of two complementary leading-edge technologies: the discovery metabolomics pipeline and the targeted/validation workflow. The discovery component features an accurate mass quadrupole time-of-flight mass spectrometer (Agilent Technologies 6520 Accurate-Mass QTOF LC/MS) that is interfaced to an Agilent Technologies 1200 series HPLC. This setup is capable of identifying and quantifying nearly all metabolites and their transient intermediates that might be present within metabolic pathways of most studies. The targeted/validation component uses an Agilent 6410 triple quadrupole LC/MS that is connected to an Agilent Technologies 1200 series HPLC to quantify and validate the metabolites identified in the discovery step, using a multiple reaction monitoring approach.

Proteomics Services

Metabolomics Services



  

Protein extraction from cell lines, tissue and biofluids; trypsin digestion

  

Co-immunoprecipitation Nano-LC/MS/MS Protein identification

LC/MS analysis of the different sample sets



XCMS differential analysis of the LC/MS analyses.



Provide XCMS output (m/z and RT) high-

teins - structural characterization of

lighting the ions that differed the most in

modified proteins, lipids and DNA in

intensity between data sets.

Provide tentative identification based on

disease – e.g. the identification and quantification of oxi-



Metabolome profiling (i.e., disease versus matched controls).

Detection and characterization of posttranslational modifications of pro-

Sample extraction and purification

 

accurate mass and mole-

dative damage to pro-

cules available in the

teins, lipids and DNA

METLIN database.

Screening for genetic mutations in proteins

Georgia Cancer Center Shared Resources

Director: Lambert C. M. Ngoka, PhD http://www.augusta.edu/cancer/research/shared/ proteomics/



Provide more firm identification based on comparative MS/MS and high accuracy analysis of 'unknown' with a standard provided by the client.

Page 73

Translational and Clinical Research

Translational and Clinical Research

OVERVIEW

Page 74

The Georgia Cancer Center at Augusta University is working toward the goal of recognition as a National Cancer Institute (NCI)-designated Cancer Center. A major expectation of the clinical trials program required to achieve this goal is to establish a program of early-phase, investigator-initiated clinical trials, demonstrating cooperation between basic scientists and clinicians in developing novel approaches for the treatment of cancer. In addition, these studies demonstrate the support that the university provides in furthering this goal.

The current listing of studies (see the following pages) constitutes ethical tissue collection studies, prevention trials, John Janik, MD NCI Community Oncology Research Program (NCORP) trials, Georgia Cancer Center Medical Director, and studies sponsored by the pharmaceutical industry. The Clinical Trials collection and analysis of tumor tissue has revealed a great deal about the mechanisms that tumors use to proliferate and metastasize and has led to the development of many targeted agents that inhibit the mutated pathways that have been identified. The Cancer Center is participating in the MATCH trial (Molecular Analysis for Therapy Choice) that has radically altered the thinking about cancer management. Whereas in the past the Cancer Center has focused on the tissue of origin of the tumor as the focus for development of drug treatment paradigms, the MATCH trial identifies mutated pathways activated in a cancer and uses the mutation as the focus for the trial.

Thus, patients with colon cancer, melanoma, or lung cancer can be treated with the same drug because of the potential for activity in a wide spectrum of tumor histologies. This approach requires sequencing tumor DNA, identifying mutations, and finally, having a drug available that targets the pathway.

Although only a minority of patients becomes eligible for treatment, successful tumor management has been observed here at the Georgia Cancer Center as well as at other treatment centers. A second major focus of the Cancer Centerâ&#x20AC;&#x2122;s clinical trial efforts is in cancer immunotherapy. This approach has added significantly to the three pillars of cancer management: surgery, radiation, and chemotherapy. Several drugs (ipilimumab, nivolumab, pembrolizumab, and atezolizumab) have been approved in patients with relapsed cancers and are now making their way into the initial management of newly diagnosed cancers.

Participation in these exciting new trials allows the Georgia Cancer Center to offer ground-breaking treatment approaches to its patients without their need to travel â&#x20AC;&#x201C; a major inconvenience for ill patients. Finally, the Cancer Centerâ&#x20AC;&#x2122;s outstanding programs in breast and gynecologic oncology are reflected by its large number of trials in these two areas. These trials offer treatment options for patients throughout the course of their cancer journey, from phase III trials investigating new approaches to management compared with the standard management to innovative phase I approaches for the treatment of patients who have exhausted other treatment options.

A Phase III Randomized Double-Blind, Controlled Study of ICT-107 with Maintenance Temozolomide (TMZ) in Newly Diagnosed Glioblastoma Following Resection and Concomitant TMZ Chemoradiotherapy

Brain

A Phase 1/2 Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of VT-464 in Patients with Advanced Breast Cancer

Breast

A Phase 2 Neoadjuvant Trial Comparing the Biological Effects of 2 Weeks of Abemaciclib (LY2835219) in Combination with Anastrozole to those of Abemaciclib Monotherapy and Anastrozole Monotherapy and Evaluating the Clinical Activity and Safety of a Subsequent 14 Weeks of Therapy with Abemaciclib in Combination with Anastrozole in Postmenopausal Women with Hormone Receptor Positive, HER2 Negative Breast Cancer

Breast

A Phase III Randomized Double-blind, Placebo Controlled Study of Alpelisib in Combination with Fulvestrant for Men and Postmenopausal Women with Hormone Receptor Positive, HER2-negative Advanced Breast Cancer which Progressed on or After Aromatase Inhibitor Treatment

Breast

Phase 2 Randomized, Double-Blinded, Controlled Study of ONT-380 vs. Placebo in Combination with Capecitabine and Trastuzumab in Patients with Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma

Breast

A Randomized Phase III Trial Comparing Axillary Lymph Node Dissection to Axillary Radiation in Breast Cancer Patients (cT1-3 N1) Who Have Positive Sentinel Lymph Node Disease After Neoadjuvant Chemotherapy

Breast

A Randomized Phase II Trial of Tamoxifen Versus Z-Endoxifen HCL in Postmenopausal Women with Metastatic Estrogen Receptor Positive, HER2 Negative Breast Cancer

Breast

A Randomized Phase III Trial of Adjuvant Therapy Comparing Doxorubicin Plus Cyclophosphamide Followed by Weekly Paclitaxel with or Without Carboplatin for Node-Positive or High-Risk Node-Negative Triple-Negative Invasive Breast Cancer

Breast

A Randomized Phase III Clinical Trial Evaluating Post-Mastectomy Chestwall and Regional Nodal XRT and Post-Lumpectomy Regional Nodal XRT in Patients with Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy

Breast

Effect of Preoperative Breast MRI on Surgical Outcomes, Costs and Quality of Life of Women with Breast Cancer

Breast

Randomized Double-Blind Placebo Controlled Study of Subcutaneous Testosterone in the Adjuvant Treatment of Postmenopausal Women with Aromatase Inhibitor Induced Arthralgias

Breast

Randomized Phase III Trial Evaluating the Role of Weight Loss in Adjuvant Treatment of Overweight and Obese Women with Early Breast Cancer

Breast

Translational and Clinical Research

Clinical Trials Opened to Accrual in 2016

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Translational and Clinical Research Page 76

(Assessment of Rucaparib In Ovarian CancEr TriaL): A Phase 3 Multicenter, Randomized Study of Rucaparib versus Chemotherapy in Patients with Relapsed, BRCA -Mutant, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Gynecological

A single arm, open-label, Phase IIb study to assess the efficacy and safety of the combination of cediranib and olaparib tablets in women with recurrent platinum resistant epithelial ovarian cancer, including fallopian tube and/or primary peritoneal cancer who do not carry a deleterious or suspected deleterious germline BRCA mutation

Gynecological

A Phase 2, Randomized Study of MLN0128 (a Dual TORC1/2 Inhibitor),MLN0128+MLN1117 (a PI3Kα Inhibitor), Weekly Paclitaxel, or the Combination of Weekly Paclitaxel and MLN0128 in Women With Advanced, Recurrent, or Persistent Endometrial Cancer

Gynecological

The MILO Study (MEK Inhibitor in Low-grade Serous Ovarian Cancer): A Multinational, Randomized, Open-label Phase 3 Study of MEK162 vs. Physician’s Choice Chemotherapy in Patients with Recurrent or Persistent Low-grade Serous Carcinomas of the Ovary, Fallopian Tube or Primary Peritoneum

Gynecological

A Multicenter, Multinational, Double-Blind, 2-Arm, Randomized, Phase 2/3, Study of Physician’s Choice Chemotherapy ([PCC] Weekly Paclitaxel or Pegylated Liposomal Doxorubicin [PLD]) Plus Bevacizumab and CA4P Versus PCC Plus Bevacizumab and Placebo for Subjects with Platinum-Resistant, Recurrent Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer

Gynecological

A Phase 3 Placebo-Controlled Study of Carboplatin/Paclitaxel With or Without Concurrent and Continuation Maintenance Veliparib (PARP inhibitor) in Subjects with Previously Untreated Stages III or IV High-Grade Serous Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Gynecological

A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients with HRD-Positive Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy

Gynecological

A Randomized, Open Label Phase 3 Study to Evaluate the Safety and Efficacy of Mirvetuximab soravtansine (IMGN853) Versus Investigator's Choice of Chemotherapy in Women with Folate Receptor Positive Advanced Epithelial Ovarian Cancer, Primary Peritoneal Cancer or Primary Fallopian Tube Cancer

Gynecological

A Randomized Phase II/III Study of Paclitaxel/Carboplatin/Metformin (NSC#91485) Versus Paclitaxel/Carboplatin/Placebo as Initial Therapy for Measurable Stage III or IVA, Stage IVB, or Recurrent Endometrial Cancer

Gynecological

A Phase III Study Comparing Single-Agent Olaparib or the Combination of Cediranib and Olaparib to Standard Platinum-Based Chemotherapy in Women with Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Gynecological

(EROS) Engendering Reproductive Health within Oncologic Survivorship

Gynecological

A Phase III Randomized, Open-label, Multi-center, Global Study of MEDI4736 Alone or in Combination with Tremelimumab versus Standard of Care in the Treatment of First-line Recurrent or Metastatic Squamous Cell Head and Neck Cancer Patients

Head & Neck

Hematological

A Phase 1 Dose-Escalation and Cohort-Expansion Study of Intravenous CBL0137 in Subjects with Previously Treated Hematological Cancers

Hematological

A Phase 1/2 Study of Vadastuximab Talirine (SGN-CD33A) in Combination with Azacitidine in Patients with Previously Untreated International Prognostic Scoring System (IPSS) Intermediate-2 or High-Risk Myelodysplastic Syndrome (MDS)

Hematological

An Open-label, Multi-center, Expanded Treatment Protocol of Midostaurin (PKC412) in Adult Patients With Newly Diagnosed Fms-like Tyrosine Kinase Receptor (FLT3) Mutated Acute Myeloid Leukemia (AML) Who Are Eligible for Standard Induction and Consolidation Chemotherapy

Leukemia

A Phase II Study of Blinatumomab (NSC-765986) and POMP (Prednisone, Vincristine, Methotrexate, 6-Mercaptopurine) for Patients >/= 65 Years of Age with Newly Diagnosed Philadelphia-Chromosome Negative (Ph-) Acute Lymphoblastic Leukemia (ALL) and of Dasatinib (NSC-732517) , Prednisone and Blinatumomab for Patients >/ = 65 Years of Age with Newly Diagnosed Philadelphia-Chromosome Positive (Ph+) ALL

Leukemia

A Phase III Randomized, Open-Label, Multi-Center, Global Study of MEDI4736 in Combination With Tremelimumab Therapy or MEDI4736 Monotherapy Versus Standard of Care Platinum-Based Chemotherapy in First Line Treatment of Patients With Advanced or Metastatic Non Small-Cell Lung Cancer (NSCLC)

Lung

An Open-Label, Single-Arm, Phase 2 Study Evaluating the Efficacy, Safety and Pharmacokinetics of Rovalpituzumab Tesirine (SC16LD6.5) for Third-Line and Later Treatment of Subjects with Relapsed or Refractory Delta-Like Protein 3-Expressing Small Cell Lung Cancer

Lung

Role of Early 18F-FDG-PET/CT Scan in Predicting Mediastinal Downstaging with Neoadjuvant Chemotherapy in Resectable Stage III A NSCLC

Lung

Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial

Lung

Randomized Double Blind Placebo Controlled Study of Erlotinib or Placebo in Patients with Completely Resected Epidermal Growth Factor Receptor (EGFR) Mutant Non-Small Cell Lung Cancer (NSCLC)

Lung

A Phase III Double-Blind Trial for Surgically Resected Early Stage Non-Small Cell Lung Cancer: Crizotinib Versus Placebo for Patients with Tumors Harboring the Anaplastic Lymphoma Kinase (ALK) Fusion Protein

Lung

Adjuvant Nivolumab in Resected Lung Cancers (ANVIL)-A Randomized Phase III Study of Nivolumab After Surgical Resection and Adjuvant Chemotherapy in Non-Small Cell Lung Cancers

Lung

A Phase 2 Study of Brentuximab Vedotin in Combination with Standard of Care Treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [RCHOP]) or RCHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) as Front-line Therapy in Patients with Diffuse Large B-cell Lymphoma (DLBCL)

Lymphoma

Phase 1/2 Study of Intratumoral G100 Therapy in Patients With Or Without Pembrolizumab In Patients With Follicular Non-Hodgkin's Lymphoma

Lymphoma

Translational and Clinical Research

A Two-Part, Multi-Center, Prospective, Phase 2/3 Clinical Study to Evaluate the Safety and Efficacy of GLASSIA as an Add-On Biopharmacotherapy to Conventional Steroid Treatment in Subjects with Acute Graft-Versus-Host Disease with Lower Gastrointestinal Involvement

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Translational and Clinical Research Page 78

A Randomized Phase III Trial of Dabrafenib + Trametinib Followed by Ipilimumab + Nivolumab at Progression vs. Ipilimumab + Nivolumab Followed by Dabrafenib + Trametinib at Progression in Patients with Advanced BRAFV600 Mutant Melanoma

Melanoma

Randomized Phase II/III Study of Nivolumab Plus Ipilimumab Plus Sargramostim Versus Nivolumab Plus Ipilimumab in Patients with Unresectable Stage III or Stage IV Melanoma

Melanoma

A Randomized Phase III Study of Brentuximab Vedotin (SGN-35, IND #117117) for Newly Diagnosed High-Risk Classical Hodgkin Lymphoma (cHL) in Children and Adolescents

Pediatric

Utilizing Response- and Biology-Based Risk Factors to Guide Therapy

Pediatric

The Project: EveryChild Protocol: A Registry, Eligibility Screening, Biology and Outcome Study

Pediatric

Use of a Clinical Screening Tool to Address Cancer Health Disparities in the NCI Community Oncology Research Program (NCORP)

Prevention

Open-label, Multicenter, Phase 1/2 Study of Mogamulizumab in Combination with Locally Advanced or Metastatic Solid Tumors

Solid Tumor

A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Clinical Activity of MEDI0562 in Adult Subjects with Selected Advanced Solid Tumors

Solid Tumor

A Phase 1 Multicenter, Open-label, Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Anti-tumor Activity of MEDI0562 in Combination With Immune Therapeutic Agents in Adult Subjects With Advanced Solid Tumors

Solid Tumor

Molecular Analysis for Therapy Choice (MATCH)

Solid tumors/ lymphoma

A Single Arm Study of SNX-5422 in Subjects With TP53 Null Cancers

TP53 Null Cell Cancers

2016 Georgia Cancer Center Publications Achyut BR, Shankar A, Iskander AS, Ara R, Knight RA, Scicli AG, Arbab AS. Chimeric Mouse model to track the migration of bone marrow derived cells in glioblastoma following anti-angiogenic treatments. Cancer Biol Ther. 2016;17(3):280-90. doi: 10.1080/15384047.2016.1139243.

Ahuja M, Ammal Kaidery N, Yang L, Calingasan N, Smirnova N, Gaisin A, Gaisina IN, Gazaryan I, Hushpulian DM, Kaddour-Djebbar I, Bollag WB, Morgan JC, Ratan RR, Starkov AA, Beal MF, Thomas B. Distinct Nrf2 Signaling Mechanisms of Fumaric Acid Esters and Their Role in Neuroprotection against 1Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Experimental Parkinson's-Like Disease. J Neurosci.

2016 Jun 8;36(23):6332-51. doi: 10.1523/JNEUROSCI.0426-16.2016.

Al-Khami AA, Rodriguez PC, Ochoa AC. Metabolic reprogramming of myeloid-derived suppressor cells (MDSC) in cancer. Oncoimmunology. 2016 Jun 27;5(8):e1200771. doi: 10.1080/2162402X.2016.1200771.

Allott EH, Howard LE, Aronson WJ, Terris MK, Kane CJ, Amling CL, Cooperberg MR, Freedland SJ. Racial Differences in the Association Between Preoperative Serum Cholesterol and Prostate Cancer Recurrence: Results from the SEARCH Database. Cancer Epidemiol Biomarkers Prev. 2016 Mar;25(3):547-54. doi: 10.1158/1055-9965.EPI-15-0876.

Andrews JO, Mueller M, Dooley M, Newman SD, Magwood GS, Tingen MS. Effect of a smoking cessation intervention for women in subsidized neighborhoods: A randomized controlled trial. Prev Med. 2016 Sep;90:170-6. doi: 10.1016/j.ypmed.2016.07.008.

Anea CB, Lyon M, Lee IA, Gonzales JN, Adeyemi A, Falls G, Kutlar A, Brittain JE. Pulmonary platelet thrombi and vascular pathology in acute chest syndrome in patients with sickle cell disease. Am J Hematol.

2016 Feb;91(2):173-8. doi: 10.1002/ajh.24224.

Angara K, Rashid MH, Shankar A, Ara R, Iskander A, Borin TF, Jain M, Achyut BR, Arbab AS. Vascular mimicry in glioblastoma following anti-angiogenic and anti-20-HETE therapies. Histol Histopathol. 2016 Dec 19:11856. doi: 10.14670/HH-11-856. [Epub ahead of print] Arjunan P, Gnanaprakasam JP, Ananth S, Romej MA, Rajalakshmi VK, Prasad PD, Martin PM, Gurusamy M, Thangaraju M, Bhutia YD, Ganapathy V. Increased Retinal Expression of the Pro-Angiogenic Receptor GPR91 via BMP6 in a Mouse Model of Juvenile Hemochromatosis. Invest Ophthalmol Vis Sci. 2016 Apr 1;57(4):1612-9. doi: 10.1167/iovs.15-17437.

Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, Guthrie TH, Knight-Madden J, Alvarez OA, Gordeuk VR, Gualandro S, Colella MP, Smith WR, Rollins SA, Stocker JW, Rother RP. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2016 Dec 3. [Epub ahead of print] Badawy SM, Black V, Meier ER, Myers KC, Pinkney K, Hastings C, Hilden JM, Zweidler-McKay P, Stork LC, Johnson TS, Vaiselbuh SR. Early career mentoring through the American Society of Pediatric Hematology/Oncology: Lessons learned from a pilot program. Pediatr Blood Cancer. 2016 Sep 12. doi: 10.1002/ pbc.26252. [Epub ahead of print]

Georgia Cancer Center 2016 Publications

Achyut BR, Arbab AS. Myeloid cell signatures in tumor microenvironment predicts therapeutic response in cancer. Onco Targets Ther. 2016 Mar 1;9:1047-55. doi: 10.2147/OTT.S102907. Review.

Barnes VA, Monto A, Williams JJ, Rigg JL. Impact of Transcendental Meditation on Psychotropic Medication Use Among Active Duty Military Service Members With Anxiety and PTSD. Mil Med. 2016 Jan;181 (1):56-63. doi: 10.7205/MILMED-D-14-00333.

Barik A, Li L, Sathyamurthy A, Xiong WC, Mei L. Schwann Cells in Neuromuscular Junction Formation and Maintenance. J Neurosci. 2016 Sep 21;36(38):9770-81. doi: 10.1523/JNEUROSCI.0174-16.2016.

Belcher MD, Kaddour-Djebbar I, Bollag WB, Davis LS. The proteolytic effect of bromelain on bullous pemphigoid antigen-2. J Am Acad Dermatol. 2016 Oct;75(4):838-40. doi: 10.1016/j.jaad.2016.05.025. No abstract available.

Page 79

Berber E, Bernet V, Fahey TJ 3rd, Kebebew E, Shaha A, Stack BC Jr, Stang M, Steward DL, Terris DJ. American Thyroid Association Statement on Remote-Access Thyroid Surgery. Thyroid. 2016 Mar;26 (3):331-7. doi: 10.1089/thy.2015.0407.

Georgia Cancer Center 2016 Publications

Bhatta A, Sangani R, Kolhe R, Toque HA, Cain M, Wong A, Howie N, Shinde R, Elsalanty M, Yao L, Chutkan N, Hunter M, Caldwell RB, Isales C, Caldwell RW, Fulzele S. Deregulation of arginase induces bone complications in high-fat/high-sucrose diet diabetic mouse model. Mol Cell Endocrinol. 2016 Feb 15;422:211-20. doi: 10.1016/j.mce.2015.12.005.

Bhutia YD, Babu E, Ramachandran S, Yang S, Thangaraju M, Ganapathy V. SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms. Biochem J. 2016 May 1;473 (9):1113-24. doi: 10.1042/BJ20150751. Review.

Bollag WB. Lipid signaling in keratinocytes: Lipin-1 plays a PArt. J Lipid Res. 2016 Apr;57(4):523-5. doi: 10.1194/jlr.C067074. No abstract available.

Bollag WB. Role of phospholipases in adrenal steroidogenesis. J Endocrinol. 2016 Apr;229(1):R29-41. doi: 10.1530/JOE-16-0007. Review.

Bonsack F 4th, Alleyne CH Jr, Sukumari-Ramesh S. Augmented expression of TSPO after intracerebral hemorrhage: a role in inflammation? J Neuroinflammation. 2016 Jun 17;13(1):151. doi: 10.1186/s12974016-0619-2.

Booth L, Albers T, Roberts JL, Tavallai M, Poklepovic A, Lebedyeva IO, Dent P. Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo. Oncotarget. 2016 Jun 28;7(26):40398-417. doi: 10.18632/oncotarget.9752.

Booth L, Shuch B, Albers T, Roberts JL, Tavallai M, Proniuk S, Zukiwski A, Wang D, Chen CS, Bottaro D, Ecroyd H, Lebedyeva IO, Dent P. Multi-kinase inhibitors can associate with heat shock proteins through their NH2-termini by which they suppress chaperone function. Oncotarget. 2016 Mar 15;7(11):12975-96. doi: 10.18632/oncotarget.7349. Published online 2016 Feb 12. doi: 10.18632/oncotarget.7349 Borin TF, Arbab AS, Gelaleti GB, Ferreira LC, Moschetta MG, Jardim-Perassi BV, Iskander A, Varma NR, Shankar A, Coimbra VB, Fabri VA, de Oliveira JG, Zuccari DA. Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression. J Pineal Res. 2016 Jan;60(1):3-15. doi: 10.1111/jpi.12270.

Boyington JE, Maihle NJ, Rice TK, Gonzalez JE, Hess CA, Makala LH, Jeffe DB, Ogedegbe G, Rao DC, Dรกvila-Romรกn VG, Pace BS, Jean-Louis G, Boutjdir M. A Perspective on Promoting Diversity in the Biomedical Research Workforce: The National Heart, Lung, and Blood Institute's PRIDE Program. Ethn Dis. 2016 Jul 21;26(3):379-86. doi: 10.18865/ed.26.3.379.

Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, Rodriguez PC, Sica A, Umansky V, Vonderheide RH, Gabrilovich DI. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun.

2016 Jul 6;7:12150. doi: 10.1038/ncomms12150. Review.

Burke J, Hunter M, Kolhe R, Isales C, Hamrick M, Fulzele S. Therapeutic potential of mesenchymal stem cell based therapy for osteoarthritis. Clin Transl Med. 2016 Dec;5(1):27. doi: 10.1186/s40169-016-0112-7.

Review.

Bustamante EE, Williams CF, Davis CL. Physical Activity Interventions for Neurocognitive and Academic Performance in Overweight and Obese Youth: A Systematic Review. Pediatr Clin North Am. 2016 Jun;63 (3):459-80. doi: 10.1016/j.pcl.2016.02.004. Review.

Bustamante EE, Davis CL, Frazier SL, Rusch D, Fogg LF, Atkins MS, Marquez DX. Randomized Controlled Trial of Exercise for ADHD and Disruptive Behavior Disorders. Med Sci Sports Exerc. 2016 Jan 30.

[Epub ahead of print] Cai Y, Singh N, Li H. Essential role of Ufm1 conjugation in the hematopoietic system. Exp Hematol. 2016 Jun;44(6):442-6. doi: 10.1016/j.exphem.2016.03.007. Review.

Page 80

Chaffin J, Lee JR, Rao SS, Sharma SJ. Two Cases of Chronic Intestinal Pseudo-obstruction: A Comparison of Staining Characteristics of Enteric Visceral Myopathy With Hirschsprung Disease. Appl Immunohistochem Mol Morphol. 2016 Sep;24(8):e72-9. doi: 10.1097/PAI.0000000000000314.

Chu X, Chen X, Wan Q, Zheng Z, Du Q. Nuclear Mitotic Apparatus (NuMA) Interacts with and Regulates Astrin at the Mitotic Spindle. J Biol Chem. 2016 Sep 16;291(38):20055-67. doi: 10.1074/jbc.M116.724831.

Chung C, Marson JD, Zhang QG, Kim J, Wu WH, Brann DW, Chen BS. Neuroprotection Mediated through GluN2C-Containing N-methyl-D-aspartate (NMDA) Receptors Following Ischemia. Sci Rep. 2016 Nov 15;6:37033. doi: 10.1038/srep37033.

Coe GL, Redd PS, Paschall AV, Lu C, Gu L, Cai H, Albers T, Lebedyeva IO, Liu K. Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor -specific cytotoxic T lymphocytes. Sci Rep. 2016 Aug 4;6:30816. doi: 10.1038/srep30816.

Colombo CJ, Baer S, Blake L, Bollag WB, Colombo R, Diamond M, George V, Huber L, Merchen L, Miles K, Yang F, Nahman NS Jr. A departmental initiative for clinical and translational research. J Investig Med. 2016 Jun;64(5):1001-5. doi: 10.1136/jim-2016-000089.

Cook TS, Krishnaraj A, Willis MH, Abbott C, Rawson JV. An Asynchronous Online Collaboration Between Radiologists and Patients: Harnessing the Power of Informatics to Design the Ideal Patient Portal. J Am Coll Radiol. 2016 Dec;13(12 Pt B):1599-1602. doi: 10.1016/j.jacr.2016.09.040. No abstract available.

Georgia Cancer Center 2016 Publications

Cancer Genome Atlas Research Network, Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, Wheeler DA, Murray BA, Schmidt L, Vocke CD, Peto M, Al Mamun AA, Shinbrot E, Sethi A, Brooks S, Rathmell WK, Brooks AN, Hoadley KA, Robertson AG, Brooks D, Bowlby R, Sadeghi S, Shen H, Weisenberger DJ, Bootwalla M, Baylin SB, Laird PW, Cherniack AD, Saksena G, Haake S, Li J, Liang H, Lu Y, Mills GB, Akbani R, Leiserson MD, Raphael BJ, Anur P, Bottaro D, Albiges L, Barnabas N, Choueiri TK, Czerniak B, Godwin AK, Hakimi AA, Ho TH, Hsieh J, Ittmann M, Kim WY, Krishnan B, Merino MJ, Mills Shaw KR, Reuter VE, Reznik E, Shelley CS, Shuch B, Signoretti S, Srinivasan R, Tamboli P, Thomas G, Tickoo S, Burnett K, Crain D, Gardner J, Lau K, Mallery D, Morris S, Paulauskis JD, Penny RJ, Shelton C, Shelton WT, Sherman M, Thompson E, Yena P, Avedon MT, Bowen J, Gastier-Foster JM, Gerken M, Leraas KM, Lichtenberg TM, Ramirez NC, Santos T, Wise L, Zmuda E, Demchok JA, Felau I, Hutter CM, Sheth M, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Zhang J, Ayala B, Baboud J, Chudamani S, Liu J, Lolla L, Naresh R, Pihl T, Sun Q, Wan Y, Wu Y, Ally A, Balasundaram M, Balu S, Beroukhim R, Bodenheimer T, Buhay C, Butterfield YS, Carlsen R, Carter SL, Chao H, Chuah E, Clarke A, Covington KR, Dahdouli M, Dewal N, Dhalla N, Doddapaneni HV, Drummond JA, Gabriel SB, Gibbs RA, Guin R, Hale W, Hawes A, Hayes DN, Holt RA, Hoyle AP, Jefferys SR, Jones SJ, Jones CD, Kalra D, Kovar C, Lewis L, Li J, Ma Y, Marra MA, Mayo M, Meng S, Meyerson M, Mieczkowski PA, Moore RA, Morton D, Mose LE, Mungall AJ, Muzny D, Parker JS, Perou CM, Roach J, Schein JE, Schumacher SE, Shi Y, Simons JV, Sipahimalani P, Skelly T, Soloway MG, Sougnez C, Tam A, Tan D, Thiessen N, Veluvolu U, Wang M, Wilkerson MD, Wong T, Wu J, Xi L, Zhou J, Bedford J, Chen F, Fu Y, Gerstein M, Haussler D, Kasaian K, Lai P, Ling S, Radenbaugh A, Van Den Berg D, Weinstein JN, Zhu J, Albert M, Alexopoulou I, Andersen JJ, Auman JT, Bartlett J, Bastacky S, Bergsten J, Blute ML, Boice L, Bollag RJ, Boyd J, Castle E, Chen YB, Cheville JC, Curley E, Davies B, DeVolk A, Dhir R, Dike L, Eckman J, Engel J, Harr J, Hrebinko R, Huang M, Huelsenbeck-Dill L, Iacocca M, Jacobs B, Lobis M, Maranchie JK, McMeekin S, Myers J, Nelson J, Parfitt J, Parwani A, Petrelli N, Rabeno B, Roy S, Salner AL, Slaton J, Stanton M, Thompson RH, Thorne L, Tucker K, Weinberger PM, Winemiller C, Zach LA, Zuna R. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N Engl J Med. 2016 Jan 14;374(2):135-45. doi: 10.1056/ NEJMoa1505917.

Cook TS, Willis MH, Abbott C, Rawson JV, Krishnaraj A. Out of the Darkness and Into the Light: Patients, Referring Physicians, and Radiologists Working Toward Patient- and Family-Centered Care in Radiology. J Am Coll Radiol. 2016 Nov 21. pii: S1546-1440(16)30806-7. doi: 10.1016/j.jacr.2016.08.030. [Epub ahead of print] No abstract available.

Cowell JK, Qin H, Chang CS, Kitamura E, Ren M. A model of BCR-FGFR1 driven human AML in immunocompromised mice. Br J Haematol. 2016 Nov;175(3):542-545. doi: 10.1111/bjh.13877. No abstract available.

Cronin P, Rawson JV. Review of Research Reporting Guidelines for Radiology Researchers. Acad Radiol.

2016 May;23(5):537-58. doi: 10.1016/j.acra.2016.01.004. Review.

Cui H, Li X, Han C, Wang QE, Wang H, Ding HF, Zhang J, Yan C. The Stress Responsive Gene ATF3 Mediates Dichotomous UV Responses by Regulating Tip60 and p53. J Biol Chem. 2016 Mar 18. pii: jbc.M115.713099. [Epub ahead of print]

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Cui Y, Guo G. Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment. Int J Mol Sci. 2016 Nov 19;17(11). pii: E1942. Review da Silva SR, Paiva SL, Bancerz M, Geletu M, Lewis AM, Chen J, Cai Y, Lukkarila JL, Li H, Gunning PT. A selective inhibitor of the UFM1-activating enzyme, UBA5. Bioorg Med Chem Lett. 2016 Sep 15;26 (18):4542-7. doi: 10.1016/j.bmcl.2015.10.015.

Georgia Cancer Center 2016 Publications

Davis CL, Tingen MS, Jia J, Sherman F, Williams CF, Bhavsar K, Wood N, Kobleur J, Waller JL. Passive Smoke Exposure and Its Effects on Cognition, Sleep, and Health Outcomes in Overweight and Obese Children. Child Obes. 2016 Apr;12(2):119-25. doi: 10.1089/chi.2015.0083.

Davis JE, Xie X, Guo J, Huang W, Chu WM, Huang S, Teng Y, Wu G. ARF1 promotes prostate tumorigenesis via targeting oncogenic MAPK signaling. Oncotarget. 2016 Jun 28;7(26): 39834-39845. doi: 10.18632/ oncotarget.9405.

Dinetz SF, Waller JL, Tingen MS. Is the association between exhaled nitric oxide and asthma symptoms altered by body weight in rural adolescents? Ann Allergy Asthma Immunol. 2016 Dec;117(6):718-719.e1. doi: 10.1016/j.anai.2016.09.431. No abstract available.

Ding ZC, Liu C, Cao Y, Habtetsion T, Kuczma M, Pi W, Kong H, Cacan E, Greer SF, Cui Y, Blazar BR, Munn DH, Zhou G. IL-7 signaling imparts polyfunctionality and stemness potential to CD4(+) T cells. Oncoimmunology. 2016 Apr 25;5(6):e1171445. doi: 10.1080/2162402X.2016.1171445.

Dinkins MB, Enasko J, Hernandez C, Wang G, Kong J, Helwa I, Liu Y, Terry AV Jr, Bieberich E. Neutral Sphingomyelinase-2 Deficiency Ameliorates Alzheimer's Disease Pathology and Improves Cognition in the 5XFAD Mouse. J Neurosci. 2016 Aug 17;36(33):8653-67. doi: 10.1523/JNEUROSCI.1429-16.2016.

Dinkins MB, Wang G, Bieberich E. Sphingolipid-Enriched Extracellular Vesicles and Alzheimer's Disease: A Decade of Research. J Alzheimers Dis. 2016 Sep 21. [Epub ahead of print] Domen RE, Johnson K, Conran RM, Hoffman RD, Post MD, Steinberg JJ, Brissette MD, Gratzinger DA, McCloskey CB, Raciti PM, Roberts CA, Rojiani AM, Powell SZ. Professionalism in Pathology: A CaseBased Approach as a Potential Educational Tool. Arch Pathol Lab Med. 2016 Oct 20.

Dou P, Zhang D, Cheng Z, Zhou G, Zhang L. PKIB promotes cell proliferation and the invasion-metastasis cascade through the PI3K/Akt pathway in NSCLC cells. Exp Biol Med (Maywood). 2016 Jun 20. pii: 1535370216655908. [Epub ahead of print] Du RH, Wu FF, Lu M, Shu XD, Ding JH, Wu G, Hu G. Uncoupling protein 2 modulation of the NLRP3 inflammasome in astrocytes and its implications in depression. Redox Biol. 2016 Oct;9:178-187. doi: 10.1016/j.redox.2016.08.006.

Duke WS, Kim AS, Waller JL, Terris DJ. Persistently elevated parathyroid hormone after successful parathyroid surgery. Laryngoscope. 2016 Aug 22. doi: 10.1002/lary.26205. [Epub ahead of print] Duke WS, Vernon HM, Terris DJ. Reoperative Parathyroidectomy: Overly Descended Superior Adenoma.

Otolaryngol Head Neck Surg. 2016 Feb;154(2):268-71. doi: 10.1177/0194599815619625.

Edhayan G, Ohara RA, Stinson WA, Amin MA, Isozaki T, Ha CM, Haines GK 3rd, Morgan R, Campbell PL, Arbab AS, Friday SC, Fox DA, Ruth JH. Inflammatory properties of inhibitor of DNA binding 1 secreted by synovial fibroblasts in rheumatoid arthritis. Arthritis Res Ther. 2016 Apr 12;18:87. doi: 10.1186/s13075016-0984-3.

Elding Larsson H, Vehik K, Haller MJ, Liu X, Akolkar B, Hagopian W, Krischer J, Lernmark Ă&#x2026;, She JX, Simell O, Toppari J, Ziegler AG, Rewers M; TEDDY Study Group. Growth and Risk for Islet Autoimmunity and Progression to Type 1 Diabetes in Early Childhood: The Environmental Determinants of Diabetes in the Young Study. Diabetes. 2016 Jul;65(7):1988-95. doi: 10.2337/db15-1180.

Fang D, Chen H, Zhu JY, Wang W, Teng Y, Ding HF, Jing Q, Su SB, Huang S. Epithelial-mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways. Oncogene. 2016 Sep 12. doi: 10.1038/onc.2016.323. [Epub ahead of print] Ferris DG. Change Suboptimal Tactics and Promote a National Mandatory Human Papillomavirus Vaccination Program. J Low Genit Tract Dis. 2016 Oct;20(4):348-351. No abstract available.

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Fischer S, Lin D, Simon RM, Howard LE, Aronson WJ, Terris MK, Kane CJ, Amling CL, Cooperberg MR, Freedland SJ, Vidal AC. Do all men with pathological Gleason score 8-10 prostate cancer have poor outcomes? Results from the SEARCH database. BJU Int. 2016 Aug;118(2):250-7. doi: 10.1111/bju.13319.

Freedland SJ, Howard LE, Hanyok BT, Kadiyala VK, Kuang JY, Whitney CA, Wilks FR, Kane CJ, Terris MK, Amling CL, Cooperberg MR, Aronson WJ, Moreira DM. Validation of a bone scan positivity risk table in non-metastatic castration-resistant prostate cancer. BJU Int. 2016 Oct;118(4):570-7. doi: 10.1111/ bju.13405.

Goodman SR, Pace BS, Hansen KC, D'alessandro A, Xia Y, Daescu O, Glatt SJ. Multiomic candidate biomarkers for clinical manifestations of sickle cell severity: Early steps to precision medicine. Exp Biol Med (Maywood). 2016 Mar 27. pii: 1535370216640150. [Epub ahead of print] Hanyok BT, Howard LE, Amling CL, Aronson WJ, Cooperberg MR, Kane CJ, Terris MK, Posadas EM, Freedland SJ. Is computed tomography a necessary part of a metastatic evaluation for castration-resistant prostate cancer? Results from the Shared Equal Access Regional Cancer Hospital Database. Cancer.

2016 Jan 15;122(2):222-9. doi: 10.1002/cncr.29748.

Hao Z, Biddinger P, Schroeder C, Tariq K. Battling regional (stage III) lung cancer: bumpy road of a cancer survivor in the immunotherapy age. BMJ Case Rep. 2016 Jul 7;2016. pii: bcr2016215304. doi: 10.1136/bcr -2016-215304.

Hao Z, Sadek I. Sunitinib: the antiangiogenic effects and beyond. Onco Targets Ther. 2016 Sep 8;9:5495505. doi: 10.2147/OTT.S112242. eCollection 2016. Review.

Harlow BL, Klaassen Z, Holzman S, Reinstatler L, Franken AA, Kavuri SK, Terris MK, Master VA, Moses KA. Multiple Discordant Histology After Nephrectomy: Descriptive Analysis and Outcomes. Clin Genitourin Cancer. 2016 Apr;14(2):e171-5. doi: 10.1016/j.clgc.2015.10.013.

Harper BT, Klaassen Z, DiBianco JM, Yaguchi G, Jen RP, Terris MK. Suicide Risk in Patients With Bladder Cancer: A Call to Action. J Wound Ostomy Continence Nurs. 2016 Mar-Apr;43(2):170-1. doi: 10.1097/ WON.0000000000000187. No abstract available.

He Y, Wu S. 2016. Chapter 20: Engineering alpha-fetoprotein to develop vaccines and T cell immunotherapies for hepatocellular carcinoma: From preclinical studies to future perspectives. In: Lakhi N, Moretti M, editors. Alpha Fetoprotein, Function and Clinical Applications. New York (NY): Nova Publishers. p. 375-91 Hoff JJ, Zhu L, Dong Y, Albers T, Steel PJ, Cui X, Wen Y, Lebedyeva I, Miao S. Diazapentacene derivatives: synthesis, properties, and structures. RSC Adv. 2016. 6:86824-8. doi:10.1039/C6RA15359C. Hong M, Ren MQ, Silva J, Paul A, Wilson WD, Schroeder C, Weinberger P, Janik J, Hao Z. YM155 inhibits topoisomerase function. Anticancer Drugs. 2016 Oct 13.

Hong Y, Manoharan I, Suryawanshi A, Shanmugam A, Swafford D, Ahmad S, Chinnadurai R, Manicassamy B, He Y, Mellor AL, Thangaraju M, Munn DH, Manicassamy S. Deletion of LRP5 and LRP6 in dendritic cells enhances antitumor immunity.

Oncoimmunology.

2016 Apr; (4): e1115941. doi: 10.1080/2162402X.2015.1115941.

Georgia Cancer Center 2016 Publications

Gao L, Teng Y. Exploiting plug-and-play electrochemistry for drug discovery. Future Med Chem. 2016 Apr;8(5):567-77. doi: 10.4155/fmc.16.8.

Hossain MA, Shen Y, Knudson I, Thakur S, Stees JR, Qiu Y, Pace BS, Peterson KR, Bungert J. Activation of Fetal Îł-globin Gene Expression via Direct Protein Delivery of Synthetic Zinc-finger DNA-Binding Domains. Mol Ther Nucleic Acids. 2016 Oct 18;5(10):e378. doi: 10.1038/mtna.2016.85.

Huang L, Ou R, Rabelo de Souza G, Cunha TM, Lemos H, Mohamed E, Li L, Pacholczyk G, Randall J, Munn DH, Mellor AL. Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase. PLoS Pathog. 2016 May 11;12(5):e1005615. doi: 10.1371/journal.ppat.1005615. eCollection 2016 May. Huang Z, Hu J, Pan J, Wang Y, Hu G, Zhou J, Mei L, Xiong WC. YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation. Development. 2016 Jul 1;143(13):2398-409. doi: 10.1242/dev.130658.

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Ishibashi K, Kumai T, Ohkuri T, Kosaka A, Nagato T, Hirata Y, Ohara K, Oikawa K, Aoki N, Akiyama N, Sado M, Kitada M, Harabuchi Y, Celis E, Kobayashi H. Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy. Oncoimmunology. 2016 Mar 30;5(6):e1169356. doi: 10.1080/2162402X.2016.1169356.

Georgia Cancer Center 2016 Publications

Islam BN, Sharman S, Bridges A, Sridhar S, Browning DB. Sildenafil Treatment Suppresses Intestinal Tumorigenesis in Mice. Gastroenterology. 2016 150(4):S625.

Itokazu Y, Tajima N, Kerosuo L, Somerharju P, Sariola H, Yu RK, Käkelä R. A2B5+/GFAP+ Cells of Rat Spinal Cord Share a Similar Lipid Profile with Progenitor Cells: A Comparative Lipidomic Study. Neurochem Res. 2016 Jul;41(7):1527-44. doi: 10.1007/s11064-016-1867-3.

Itokazu Y, Tsai YT, Yu RK. Epigenetic regulation of ganglioside expression in neural stem cells and neuronal cells. Glycoconj J. 2016 Aug 19. [Epub ahead of print] Review.

Jacobi SK, Yatsunenko T, Li D, Dasgupta S, Yu RK, Berg BM, Chichlowski M, Odle J. Dietary Isomers of Sialyllactose Increase Ganglioside Sialic Acid Concentrations in the Corpus Callosum and Cerebellum and Modulate the Colonic Microbiota of Formula-Fed Piglets. J Nutr. 2016 Feb;146(2):200-8. doi: 10.3945/ jn.115.220152.

Jaja C, Barrett N, Patel N, Lyon M, Xu H, Kutlar A. Progressing Preemptive Genotyping of CYP2C19 Allelic Variants for Sickle Cell Disease Patients. Genet Test Mol Biomarkers. 2016 Oct;20(10):609-615.

Johnson C, Sheshadri P, Ketchum JM, Narayanan LK, Weinberger PM, Shirwaiker RA. In vitro characterization of design and compressive properties of 3D-biofabricated/decellularized hybrid grafts for tracheal tissue engineering. J Mech Behav Biomed Mater. 2016 Jun;59:572-85. doi: 10.1016/j.jmbbm.2016.03.024.

Johnson CM, Howell JT, Mettenburg DJ, Rueggeberg FA, Howell RJ, Postma GN, Weinberger PM. Mechanical Modeling of the Human Cricoid Cartilage Using Computer-Aided Design: Applications in Airway Balloon Dilation Research.

Ann Otol Rhinol Laryngol.

2016 Jan;125(1):69-76. doi: 10.1177/0003489415598999.

Johnson T, Giller C, Heger I, Kennedy E, Kolhe R, Mourad W, Rojiani A, Sadek R, Vahanian N, Macdonald T, Munn D. Phase 1 Trial of indoximod in combination with temozolomide-based therapy for children with progressive primary brain tumors. (NCT02502708). Pediatr Blood Cancer. 2016 63:S72-S73.

Johnson TS, McGaha T, Munn DH. Chemo-immunotherapy: impact of indoleamine 2,3-dioxygenase in defining immunogenic versus tolerogenic cell death in the tumor microenvironment. In Kalinski P (Ed.): The Microenvironment in Cancer Progression and Cancer Therapy. Springer (2016).

Johnson TS, Munn DH. Overcoming immune suppression in the tumor microenvironment: implications for multi-modal therapy. In: Gray JC, Marabelle A (Eds.) Immunotherapy for Paediatric Malignancies. (in press): Springer.

Jordan AR, Lokeshwar SD, Lopez LE, Hennig M, Chipollini J, Yates T, Hupe MC, Merseburger AS, Shiedlin A, Cerwinka WH, Liu K, Lokeshwar VB. Antitumor activity of sulfated hyaluronic acid fragments in preclinical models of bladder cancer. Oncotarget. 2016 Jul 11. doi: 10.18632/oncotarget.10529. [Epub ahead of print] Kabaria R, Klaassen Z, Terris MK. Renal cell carcinoma: links and risks. Int J Nephrol Renovasc Dis. 2016 Mar 7;9:45-52. doi: 10.2147/IJNRD.S75916. eCollection 2016. Review.

Kallifatidis G, Hoy JJ, Lokeshwar BL. Bioactive natural products for chemoprevention and treatment of castration-resistant prostate cancer. Semin Cancer Biol. 2016 Oct;40-41:160-169. doi: 10.1016/ j.semcancer.2016.06.003. Review.

Kallifatidis G, Munoz D, Singh RK, Salazar N, Hoy JJ, Lokeshwar BL. β-Arrestin-2 Counters CXCR7Mediated EGFR Transactivation and Proliferation. Mol Cancer Res. 2016 May;14(5):493-503. doi: 10.1158/1541-7786.MCR-15-0498.

Kandasamy M, Suryawanshi A, Tundup S, Perez JT, Schmolke M, Manicassamy S, Manicassamy B. RIG-I Signaling Is Critical for Efficient Polyfunctional T Cell Responses during Influenza Virus Infection. PLoS Pathog. 2016 Jul 20;12(7):e1005754. doi: 10.1371/journal.ppat.1005754. eCollection 2016 Jul.

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Kaufman HL, Butterfield LH, Coulie PG, Demaria S, Ferris RL, Galon J, Khleif SN, Mellman I, Ohashi PS, Overwijk WW, Topalian SL, Marincola FM. Society for immunotherapy of cancer (SITC) statement on the proposed changes to the common rule. J Immunother Cancer. 2016 Jun 21;4:37. doi: 10.1186/s40425-016 -0142-0. eCollection 2016.

Kemppainen KM, Lynch KF, Liu E, Lönnrot M, Simell V, Briese T, Koletzko S, Hagopian W, Rewers M, She JX, Simell O, Toppari J, Ziegler AG, Akolkar B, Krischer JP, Lernmark Å, Hyöty H, Triplett EW, Agardh D; TEDDY Study Group.. Factors that Increase Risk of Celiac Disease Autoimmunity Following a Gastrointestinal Infection in Early Life. Clin Gastroenterol Hepatol. 2016 Nov 10. pii: S1542-3565(16)31043-6. doi: 10.1016/j.cgh.2016.10.033. [Epub ahead of print] Kim S, Campbell J, Yoo W, Taylor JA, Sandler DP. Systemic levels of estrogens and PGE2 synthesis in relation to postmenopausal breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2016 Nov 18. pii: cebp.0556.2016. [Epub ahead of print] Klaassen Z, DiBianco JM, Jen RP, Evans AJ, Reinstatler L, Terris MK, Madi R. Female, Black, and Unmarried Patients Are More Likely to Present With Metastatic Bladder Urothelial Carcinoma. Clin Genitourin Cancer. 2016 Oct;14(5):e489-e492. doi: 10.1016/j.clgc.2016.04.006.

Klaassen Z, DiBianco JM, Jen RP, Harper B, Yaguchi G, Reinstatler L, Woodard C, Moses KA, Terris MK, Madi R. The Impact of Radical Cystectomy and Urinary Diversion on Suicidal Death in Patients With Bladder Cancer. J Wound Ostomy Continence Nurs. 2016 Mar-Apr;43(2):152-7. doi: 10.1097/ WON.0000000000000188.

Klaassen Z, Howard LE, de Hoedt A, Amling CL, Aronson WJ, Cooperberg MR, Kane CJ, Terris MK, Freedland SJ. Factors predicting skeletal-related events in patients with bone metastatic castrationresistant prostate cancer. Cancer. 2016 Dec 27. doi: 10.1002/cncr.30505. [Epub ahead of print] Klaassen Z, Howard LE, Moreira DM, Andriole GL Jr, Terris MK, Freedland SJ. Association of ObesityRelated Hemodilution of Prostate-Specific Antigen, Dihydrotestosterone, and Testosterone. Prostate. 2016 Dec 19. doi: 10.1002/pros.23285. [Epub ahead of print] Klaassen Z, Reinstatler L, Wilson SN, Ellington C, Li Q, Terris MK, Moses KA. Clinical Disparities for Minorities and Foreign-Born Men With Undescended Versus Descended Testicular Germ Cell Tumors. Clin Genitourin Cancer. 2016 Jun;14(3):e251-5. doi: 10.1016/j.clgc.2015.08.004.

Knapp E, Cohen H, Kutlar A, Ghalie R, Manwani D. Intrapatient variability in fetal hemoglobin measurements over time in sickle cell patients not on fetal hemoglobin inducing agents. Am J Hematol. 2016 Mar;91(3):E11-2. doi: 10.1002/ajh.24261. No abstract available.

Kong H, Tang SC. Chemotherapy for Breast Cancer During Pregnancy, With Neonatal Lupus in the Newborn. Oncology (Williston Park). 2016 Jun;30(6). pii: 217522. No abstract available.

Kruse CA, Pardo CA, Hartman AL, Jallo G, Vining EP, Voros J, Gaillard WD, Liu J, Oluigbo C, Malone S, Bleasel AF, Dexter M, Micati A, Velasco TR, Machado HR, Martino AM, Huang A, Wheatley BM, Grant GA, Granata T, Freri E, Garbelli R, Koh S, Nordli DR, Campos AR, O'Neill B, Handler MH, Chapman KE, Wilfong AA, Curry DJ, Yaun A, Madsen JR, Smyth MD, Mercer D, Bingaman W, Harvey AS, Leventer RJ, Lockhart PJ, Gillies G, Pope K, Giller CA, Park YD, Rojiani AM, Sharma SJ, Jenkins P, Tung S, Huynh MN, Chirwa TW, Cepeda C, Levine MS, Chang JW, Owens GC, Vinters HV, Mathern GW. Rasmussen encephalitis tissue transfer program. Epilepsia. 2016 Jun;57(6):1005-7. doi: 10.1111/epi.13383. No abstract available.

Georgia Cancer Center 2016 Publications

Keegan PM, Anbazhakan S, Kang B, Pace BS, Platt MO. Biomechanical and biochemical regulation of cathepsin K expression in endothelial cells converge at AP-1 and NF-κB. Biol Chem. 2016 May 1;397 (5):459-68. doi: 10.1515/hsz-2015-0244.

Kuczma M, Ding ZC, Zhou G. Immunostimulatory Effects of Melphalan and Usefulness in Adoptive Cell Therapy with Antitumor CD4+ T Cells. Crit Rev Immunol. 2016;36(2):179-191.

Kumai T, Celis E, Rodriguez PC. Editorial: A matter of survival: HMGB1 regulates autophagy in tumor MDSC. J Leukoc Biol. 2016 Sep;100(3):447-9. doi: 10.1189/jlb.3CE0216-091R. No abstract available.

Kumai T, Kobayashi H, Harabuchi Y, Celis E. Peptide vaccines in cancer-old concept revisited. Curr Opin Immunol. 2016 Dec 8;45:1-7. doi: 10.1016/j.coi.2016.11.001. [Epub ahead of print] Review.

Page 85

Kumai T, Lee S, Cho HI, Sultan H, Kobayashi H, Harabuchi Y, Celis E. Optimization of Peptide Vaccines to Induce Robust Antitumor CD4 T-cell Responses. Cancer Immunol Res. 2017 Jan;5(1):72-83. doi: 10.1158/2326-6066.CIR-16-0194.

Kuraganti G, Harper RJ, Pucar D, Homlar KC, Williams HT. VISUAL VIGNETTE. Endocr Pract. 2016 Nov;22(11):1361. No abstract available.

Georgia Cancer Center 2016 Publications

Kurago ZB. Etiology and pathogenesis of oral lichen planus: an overview. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 Jul;122(1):72-80. doi: 10.1016/j.oooo.2016.03.011. Review.

Kushwaha G, Dozmorov M, Wren JD, Qiu J, Shi H, Xu D. Hypomethylation coordinates antagonistically with hypermethylation in cancer development: a case study of leukemia. Hum Genomics. 2016 Jul 25;10 Suppl 2:18. doi: 10.1186/s40246-016-0071-5.

Larsson HE, Vehik K, Haller MJ, Liu X, Akolkar B, Hagopian W, Krischer J, Lernmark Ă&#x2026;, She JX, Simell O, Toppari J, Ziegler AG, Rewers M; TEDDY study. Growth and risk for islet autoimmunity and progression to type 1 diabetes in early childhood: The Environmental Determinants of Diabetes in the Young Study. Diabetes. 2016 Mar 18. pii: db151180. [Epub ahead of print] Leapman MS, Freedland SJ, Aronson WJ, Kane CJ, Terris MK, Walker K, Amling CL, Carroll PR, Cooperberg MR. Pathological and Biochemical Outcomes among African-American and Caucasian Men with Low Risk Prostate Cancer in the SEARCH Database: Implications for Active Surveillance Candidacy. J Urol.

2016 Nov;196(5):1408-1414. doi: 10.1016/j.juro.2016.06.086.

Lembo A, Pimentel M, Rao SS, Schoenfeld P, Cash B, Weinstock LB, Paterson C, Bortey E, Forbes WP. Repeat Treatment With Rifaximin Is Safe and Effective in Patients With Diarrhea-Predominant Irritable Bowel Syndrome. Gastroenterology. 2016 Dec;151(6):1113-1121. doi: 10.1053/j.gastro.2016.08.003.

Lemos H, Mohamed E, Huang L, Ou R, Pacholczyk G, Arbab AS, Munn D, Mellor AL. STING promotes the growth of tumors characterized by low antigenicity via IDO activation. Cancer Res. 2016 Apr 15;76(8):2076 -81. doi: 10.1158/0008-5472.CAN-15-1456.

Lewis K, Reicher MA. Web Applications for Patient Communication. J Am Coll Radiol. 2016 Dec;13(12 Pt B):1603-1607. doi: 10.1016/j.jacr.2016.09.013.

Li D, Usuki S, Quarles B, Rivner MH, Ariga T, Yu RK. Anti-Sulfoglucuronosyl Paragloboside Antibody: A Potential Serologic Marker of Amyotrophic Lateral Sclerosis. ASN Neuro. 2016 Sep 28;8(5). pii: 1759091416669619. Print 2016 Oct. Linklater ES, Tovar EA, Essenburg CJ, Turner L, Madaj Z, Winn ME, Melnik MK, Korkaya H, Maroun CR, Christensen JG, Steensma MR, Boerner JL, Graveel CR. Targeting MET and EGFR crosstalk signaling in triple-negative breast cancers. Oncotarget. 2016 Sep 16. doi: 10.18632/oncotarget.12065. [Epub ahead of print] Liu F, Li X, Lu C, Bai A, Bielawski J, Bielawska A, Marshall B, Schoenlein PV, Lebedyeva IO, Liu K. Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to suppress myeloid-derived suppressor cells. Oncotarget. 2016 Dec 20;7(51):83907-25. doi: 10.18632/ oncotarget.13438.

Liu F, Tai A, Lee P, Biswas T, Ding GX, El Naqa I, Grimm J, Jackson A, Kong FS, LaCouture T, Loo B Jr, Miften M, Solberg T, Li XA. Tumor control probability modeling for stereotactic body radiation therapy of early-stage lung cancer using multiple bio-physical models. Radiother Oncol. 2016 Nov 18. pii: S01678140(16)34381-X. doi: 10.1016/j.radonc.2016.11.006. [Epub ahead of print] Review.

Liu HY, Yu X, Liu H, Wu D, She JX. Co-targeting EGFR and survivin with a bivalent aptamer-dual siRNA chimera effectively suppresses prostate cancer. Sci Rep. 2016 Jul 26;6:30346. doi: 10.1038/srep30346.

Liu L, Pertsemlidis A, Ding LH, Story MD, Steinberg MH, Sebastiani P, Hoppe C, Ballas SK, Pace BS. A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease. Exp Biol Med (Maywood). 2016 Mar 27. pii: 1535370216642047. [Epub ahead of print] Liu M, Xia Y, Ding J, Ye B, Zhao E, Choi JH, Alptekin A, Yan C, Dong Z, Huang S, Yang L, Cui H, Zha Y, Ding HF. Transcriptional Profiling Reveals a Common Metabolic Program in High-Risk Human Neuroblastoma and Mouse Neuroblastoma Sphere-Forming Cells. Cell Rep. 2016 Oct 4;17(2):609-623. doi: 10.1016/ j.celrep.2016.09.021.

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Livingston MJ, Ding HF, Huang S, Hill JA, Yin XM, Dong Z. Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction. Autophagy. 2016 Jun 2;12(6):976-98. doi: 10.1080/15548627.2016.1166317.

López M, Bollag RJ, Yu JC, Isales CM, Eroglu A. Chemically Defined and Xeno-Free Cryopreservation of Human Adipose-Derived Stem Cells. PLoS One. 2016 Mar 24;11(3):e0152161. doi: 10.1371/ journal.pone.0152161. eCollection 2016.

Lu Y, Hippen KL, Lemire AL, Gu J, Wang W, Ni X, Ranganathan P, Levine BL, Riley JL, June CH, Turka LA, Munn DH, Garzon R, Lu L, Blazar BR. miR-146b antagomir-treated human Tregs acquire increased GVHD inhibitory potency. Blood. 2016 Sep 8;128(10):1424-35. doi: 10.1182/blood-2016-05-714535.

Lucas R, Yue Q, Alli A, Duke BJ, Al-Khalili O, Thai TL, Hamacher J, Sridhar S, Lebedyeva I, Su H, Tzotzos S, Fischer B, Gameiro AF, Loose M, Chakraborty T, Shabbir W, Aufy M, Lemmens-Gruber R, Eaton DC, Czikora I. The Lectin-like Domain of TNF Increases ENaC Open Probability through a Novel Site at the Interface between the Second Transmembrane and C-terminal Domains of the α-Subunit. J Biol Chem.

2016 Nov 4;291(45):23440-23451.

Luque JS, Maupin JN, Ferris DG, Guevara Condorhuaman WS. Reaching women in the Peruvian Andes through cervical cancer screening campaigns: assessing attitudes of stakeholders and patients. Patient Prefer Adherence. 2016 Oct 18;10:2107-2116.

Luque JS, Opoku S, Ferris DG, Guevara Condorhuaman WS. Social network characteristics and cervical cancer screening among Quechua women in Andean Peru. BMC Public Health. 2016 Feb 24;16(1):181. doi: 10.1186/s12889-016-2878-3.

Luque JS, Tarasenko YN, Reyes-Garcia C, Alfonso ML, Suazo N, Rebing L, Ferris DG. Salud es Vida: a Cervical Cancer Screening Intervention for Rural Latina Immigrant Women. J Cancer Educ. 2016 Jan 12.

[Epub ahead of print] Manoharan I, Suryawanshi A, Hong Y, Ranganathan P, Shanmugam A, Ahmad S, Swafford D, Manicassamy B, Ramesh G, Koni PA, Thangaraju M, Manicassamy S. Homeostatic PPARα Signaling Limits Inflammatory Responses to Commensal Microbiota in the Intestine. J Immunol. 2016 Jun 1;196(11):4739-49. doi: 10.4049/jimmunol.1501489.

Mason E, Rompaey JV, Solares CA, Figueroa R, Prevedello D. Subtemporal Retrolabyrinthine (Posterior Petrosal) versus Endoscopic Endonasal Approach to the Petroclival Region: An Anatomical and Computed Tomography Study. J Neurol Surg B Skull Base. 2016 Jun;77(3):231-7. doi: 10.1055/s-0035-1566123.

McDonald-Hyman C, Flynn R, Panoskaltsis-Mortari A, Peterson N, MacDonald KP, Hill GR, Luznik L, Serody JS, Murphy WJ, Maillard I, Munn DH, Turka LA, Koreth J, Cutler CS, Soiffer RJ, Antin JH, Ritz J, Blazar BR. Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner. Blood. 2016 Aug 18;128(7):1013-7. doi: 10.1182/blood-2016-05-715896.

McGinley KF, Sun X, Howard LE, Aronson WJ, Terris MK, Kane CJ, Amling CL, Cooperberg MR, Freedland SJ. Utilization and impact of surgical technique on the performance of pelvic lymph node dissection at radical prostatectomy: Results from the Shared Equal Access Regional Cancer Hospital database. Int J Urol. 2016 Mar;23(3):241-6. doi: 10.1111/iju.13027.

Georgia Cancer Center 2016 Publications

Lu C, Makala L, Wu D, Cai Y. Targeting translation: eIF4E as an emerging anticancer drug target. Expert Rev Mol Med. 2016 Jan 18;18:e2. doi: 10.1017/erm.2015.20.

Mithal P, Howard LE, Aronson WJ, Terris MK, Cooperberg MR, Kane CJ, Amling C, Freedland SJ. Positive surgical margins in radical prostatectomy patients do not predict long-term oncological outcomes: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort. BJU Int. 2016 Feb;117(2):2448. doi: 10.1111/bju.13181.

Mohamed R, Jayakumar C, Chen F, Fulton D, Stepp D, Gansevoort RT, Ramesh G. Low-Dose IL-17 Therapy Prevents and Reverses Diabetic Nephropathy, Metabolic Syndrome, and Associated Organ Fibrosis. J Am Soc Nephrol. 2016 Mar;27(3):745-65. doi: 10.1681/ASN.2014111136.

Moreira DM, Howard LE, Sourbeer KN, Amarasekara HS, Chow LC, Cockrell DC, Hanyok BT, Aronson WJ, Kane CJ, Terris MK, Amling CL, Cooperberg MR, Liede A, Freedland SJ. Predictors of Time to Metastasis in Castration-resistant Prostate Cancer. Urology. 2016 Oct;96:171-176. doi: 10.1016/ j.urology.2016.06.011.

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Munn DH, Bronte V. Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol. 2016 Apr;39:1-6. doi: 10.1016/j.coi.2015.10.009. Review.

Munn DH, Mellor AL. IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance. Trends Immunol. 2016 Mar;37(3):193-207. doi: 10.1016/j.it.2016.01.002. Review.

Georgia Cancer Center 2016 Publications

Nakajima W, Sharma K, Lee JY, Maxim NT, Hicks MA, Vu TT, Luu A, Yeudall WA, Tanaka N, Harada H. DNA damaging agent-induced apoptosis is regulated by MCL-1 phosphorylation and degradation mediated by the Noxa/MCL-1/CDK2 complex. Oncotarget. 2016 Jun 14;7(24):36353-36365. doi: 10.18632/ oncotarget.9217.

Neiswender H, Navarre S, Kozlowski DJ, LeMosy EK. Early Craniofacial Defects in Zebrafish That Have Reduced Function of a Wnt-Interacting Extracellular Matrix Protein, Tinagl1. Cleft Palate Craniofac J. 2016 May 31. [Epub ahead of print] Nguyen-Lefebvre AT, Ajith A, Portik-Dobos V, Horuzsko DD, Mulloy LL, Horuzsko A. Mouse models for studies of HLA-G functions in basic science and pre-clinical research. Hum Immunol. 2016 Sep;77(9):7119. doi: 10.1016/j.humimm.2016.02.012.

Orme-Johnson DW, Barnes VA. Comment on "Meditation Programs for Psychological Stress and WellBeing". J Altern Complement Med. 2016 Dec 13. [Epub ahead of print] No abstract available.

Paholak HJ, Stevers NO, Chen H, Burnett JP, He M, Korkaya H, McDermott SP, Deol Y, Clouthier SG, Luther T, Li Q, Wicha MS, Sun D. Elimination of epithelial-like and mesenchymal-like breast cancer stem cells to inhibit metastasis following nanoparticle-mediated photothermal therapy. Biomaterials. 2016 Oct;104:145-57. doi: 10.1016/j.biomaterials.2016.06.045.

Pantin J, Purev E, Tian X, Cook L, Donohue-Jerussi T, Cho E, Reger R, Hsieh M, Khuu H, Calandra G, Geller NL, Childs RW. Effect of high-dose plerixafor on CD34+ cells mobilization in healthy stem-cell donors: results of a randomized crossover trial. Haematologica. 2016 Oct 20. pii: haematol.2016.147132.

[Epub ahead of print] Paschall AV, Yang D, Lu C, Redd PS, Choi JH, Heaton CM, Lee JR, Nayak-Kapoor A, Liu K. CD133+CD24lo defines a 5-Fluorouracil-resistant colon cancer stem cell-like phenotype. Oncotarget. 2016 Sep 21. doi: 10.18632/oncotarget.12168. [Epub ahead of print] Pathania AS, Guru SK, Kumar S, Kumar A, Ahmad M, Bhushan S, Sharma PR, Mahajan P, Shah BA, Sharma S, Nargotra A, Vishwakarma R, Korkaya H, Malik F. Interplay between cell cycle and autophagy induced by boswellic acid analog. Sci Rep. 2016 Sep 29;6:33146. doi: 10.1038/srep33146.

Pathania R, Ramachandran S, Mariappan G, Thakur P, Shi H, Choi JH, Manicassamy S, Kolhe R, Prasad PD, Sharma S, Lokeshwar BL, Ganapathy V, Thangaraju M. Combined Inhibition of DNMT and HDAC Blocks the Tumorigenicity of Cancer Stem-like Cells and Attenuates Mammary Tumor Growth. Cancer Res. 2016 Jun 1;76(11):3224-35. doi: 10.1158/0008-5472.CAN-15-2249.

Peard L, Falkenstrom A, Klaassen Z, Terris MK. Re: Mental Health Outcomes in Elderly Men with Prostate Cancer. Eur Urol. 2016 Jul;70(1):206-7. doi: 10.1016/j.eururo.2016.03.061. No abstract available.

Philpott H, Yu S, Rao S. It's All in the Mix: Diagnosis and Management of Food Intolerance. Clin Gastroenterol Hepatol. 2016 Aug;14(8):1221-2. doi: 10.1016/j.cgh.2016.03.005. No abstract available.

Piao Y, Lee SK, Lee EJ, Robertson KD, Shi H, Ryu KH, Choi JH. CAME: Identification of Chromatin Accessibility from Nucleosome Occupancy and Methylome Sequencing. Bioinformatics. 2016 Dec 29. pii: btw785. doi: 10.1093/bioinformatics/btw785. [Epub ahead of print] Powell MR, Sheehan DJ, Kleven DT. Altered Morphology and Immunohistochemical Characteristics in Metastatic Malignant Melanoma After Therapy With Vemurafenib. Am J Dermatopathol. 2016 Sep;38 (9):e137-9. doi: 10.1097/DAD.0000000000000619.

Pu F, Salarian M, Xue S, Qiao J, Feng J, Tan S, Patel A, Li X, Mamouni K, Hekmatyar K, Zou J, Wu D, Yang JJ. Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI. Nanoscale. 2016 Jul 7;8(25):12668-82. doi: 10.1039/c5nr09071g.

Page 88

Qin H, Malek S, Cowell JK, Ren M. Transformation of human CD34+ hematopoietic progenitor cells with DEK-NUP214 induces AML in an immunocompromised mouse model. Oncogene. 2016 Oct 27;35 (43):5686-91. doi: 10.1038/onc.2016.118.

Qin H, Wu Q, Cowell JK, Ren M. FGFR1OP2-FGFR1 induced myeloid leukemia and T-cell lymphoma in a mouse model. Haematologica. 2016 Mar;101(3):e91-4. doi: 10.3324/haematol.2015.137695. No abstract available.

Raber PL, Sierra RA, Thevenot PT, Shuzhong Z, Wyczechowska DD, Kumai T, Celis E, Rodriguez PC. T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy. Oncotarget. 2016 Apr 5;7(14):17565-78. doi: 10.18632/oncotarget.8197.

Rao SS, Rattanakovit K, Patcharatrakul T. Diagnosis and management of chronic constipation in adults.

Nat Rev Gastroenterol Hepatol. 2016 May;13(5):295-305. doi: 10.1038/nrgastro.2016.53. Review.

Rawson JV, Cronin P. Health Services Research Tools for the Next Generation of Radiologists. Acad Radiol. 2016 May;23(5):527-8. doi: 10.1016/j.acra.2016.02.010. No abstract available.

Rawson JV, Kannan A, Furman M. Use of Process Improvement Tools in Radiology. Curr Probl Diagn Radiol. 2016 Mar-Apr;45(2):94-100. doi: 10.1067/j.cpradiol.2015.09.004. Review.

Rawson JV, Kitts AB, Carlos RC. Patient- and Family-Centered Care: Why Radiology? J Am Coll Radiol.

2016 Dec;13(12 Pt B):1541-1542. doi: 10.1016/j.jacr.2016.09.041. No abstract available.

Rawson JV, Mitchell L, Golden L, Murdock A, Haines GR. Lessons Learned From Two Decades of Patientand Family-Centered Care in Radiology, Part 2: Building a Culture. J Am Coll Radiol. 2016 Dec;13(12 Pt B):1560-1565. doi: 10.1016/j.jacr.2016.09.011.

Rawson JV, Moretz J. Patient- and Family-Centered Care: A Primer. J Am Coll Radiol. 2016 Dec;13(12 Pt B):1544-1549. doi: 10.1016/j.jacr.2016.09.003.

Ren M, Qin H, Wu Q, Savage NM, George TI, Cowell JK. Development of ZMYM2-FGFR1 driven AML in human CD34+ cells in immunocompromised mice. Int J Cancer. 2016 Aug 15;139(4):836-40. doi: 10.1002/ ijc.30100.

Rezaie A, Pimentel M, Rao SS. How to Test and Treat Small Intestinal Bacterial Overgrowth: an EvidenceBased Approach. Curr Gastroenterol Rep. 2016 Jan;18(2):8. doi: 10.1007/s11894-015-0482-9.

Rimando J, Campbell J, Kim JH, Tang SC, Kim S. The Pretreatment Neutrophil/Lymphocyte Ratio Is Associated with All-Cause Mortality in Black and White Patients with Non-metastatic Breast Cancer. Front Oncol. 2016 Mar 31;6:81. doi: 10.3389/fonc.2016.00081. eCollection 2016.

Rosenkrantz AB, Rawson JV. Trends in Publications in Radiology Journals Designated as Relating to Patient-Centered Care. J Am Coll Radiol. 2016 Dec 21. pii: S1546-1440(16)30918-8. doi: 10.1016/ j.jacr.2016.09.016. [Epub ahead of print] Rosenstein BS, Capala J, Efstathiou JA, Hammerbacher J, Kerns SL, Kong FM, Ostrer H, Prior FW, Vikram B, Wong J, Xiao Y. How Will Big Data Improve Clinical and Basic Research in Radiation Therapy?

Int J Radiat Oncol Biol Phys. 2016 Jul 1;95(3):895-904. doi: 10.1016/j.ijrobp.2015.11.009. No abstract available.

Georgia Cancer Center 2016 Publications

Rao SS, Patcharatrakul T. Diagnosis and Treatment of Dyssynergic Defecation. J Neurogastroenterol Motil. 2016 Jul 30;22(3):423-35. doi: 10.5056/jnm16060. Review.

Ryu D, Xu H, George V, Su S, Wang X, Shi H, Podolsky RH. Differential methylation tests of regulatory regions. Stat Appl Genet Mol Biol. 2016 Jun 1;15(3):237-51. doi: 10.1515/sagmb-2015-0037.

Saha A, O'Connor RS, Thangavelu G, Lovitch SB, Dandamudi DB, Wilson CB, Vincent BG, Tkachev V, Pawlicki JM, Furlan SN, Kean LS, Aoyama K, Taylor PA, Panoskaltsis-Mortari A, Foncea R, Ranganathan P, Devine SM, Burrill JS, Guo L, Sacristan C, Snyder NW, Blair IA, Milone MC, Dustin ML, Riley JL, Bernlohr DA, Murphy WJ, Fife BT, Munn DH, Miller JS, Serody JS, Freeman GJ, Sharpe AH, Turka LA, Blazar BR. Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. J Clin Invest. 2016 Jul 1;126(7):2642-60. doi: 10.1172/JCI85796.

Sattin RW, Williams LB, Dias J, Garvin JT, Marion L, Joshua TV, Kriska A, Kramer MK, Narayan KM. Community Trial of a Faith-Based Lifestyle Intervention to Prevent Diabetes Among African-Americans. J Community Health. 2016 Feb;41(1):87-96. doi: 10.1007/s10900-015-0071-8.

Segel JM, Duke WS, White JR, Waller JL, Terris DJ. Outpatient thyroid surgery: Safety of an optimized protocol in more than 1,000 patients. Surgery. 2016 Feb;159(2):518-23. doi: 10.1016/j.surg.2015.08.007.

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Shalaby SM, Khater MK, Perucho AM, Mohamed SA, Helwa I, Laknaur A, Lebedyeva I, Liu Y, Diamond MP, Al-Hendy AA. Magnetic nanoparticles as a new approach to improve the efficacy of gene therapy against differentiated human uterine fibroid cells and tumor-initiating stem cells. Fertil Steril. 2016 Jun;105 (6):1638-1648.e8. doi: 10.1016/j.fertnstert.2016.03.001.

Georgia Cancer Center 2016 Publications

Shamaladevi N, Araki S, Lyn DA, Ayyathurai R, Gao J, Lokeshwar VB, Navarrete H, Lokeshwar BL. The andean anticancer herbal product BIRM causes destabilization of androgen receptor and induces caspase8 mediated-apoptosis in prostate cancer. Oncotarget. 2016 Oct 1. doi: 10.18632/oncotarget.12393.

Shankar A, Borin TF, Iskander A, Varma NR, Achyut BR, Jain M, Mikkelsen T, Guo AM, Chwang WB, Ewing JR, Bagher-Ebadian H, Arbab AS. Combination of vatalanib and a 20-HETE synthesis inhibitor results in decreased tumor growth in an animal model of human glioma. Onco Targets Ther. 2016 Mar 9;9:1205-19. doi: 10.2147/OTT.S93790.

Shankar A, Jain M, Lim MJ, Angara K, Arbab SA, Asm I, Ara R, Arbab AS, Achyut B. Anti-VEGFR2 Driven Nuclear Translocation of VEGFR2 and Acquired Malignant Hallmarks are Mutation Dependent in Glioblastoma. J Cancer Sci Ther 2016 8: 172-8. doi:10.4172/1948-5956.1000410.

Sharma A, Liu X, Hadley D, Hagopian W, Liu E, Chen WM, Onengut-Gumuscu S, Simell V, Rewers M, Ziegler AG, Lernmark Ă&#x2026;, Simell O, Toppari J, Krischer JP, Akolkar B, Rich SS, Agardh D, She JX; TEDDY Study Group. Identification of Non-HLA Genes Associated with Celiac Disease and Country-Specific Differences in a Large, International Pediatric Cohort. PLoS One. 2016 Mar 25;11(3):e0152476. doi: 10.1371/ journal.pone.0152476. eCollection 2016.

Sharma A, Purohit S, Sharma S, Bai S, Zhi W, Ponny SR, Hopkins D, Steed L, Bode B, Anderson SW, She JX. IGF-Binding Proteins in Type-1 Diabetes Are More Severely Altered in the Presence of Complications.

Front Endocrinol (Lausanne). 2016 Jan 29;7:2. doi: 10.3389/fendo.2016.00002. eCollection 2016.

Sharma BK, Kolhe R, Black SM, Keller JR, Mivechi NF, Satyanarayana A. Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells. FASEB J. 2016 Jan;30(1):262-75. doi: 10.1096/fj.15-277749.

Sharman S, Islam BN, Bridges A, Sridhar S, Browning DB. Sildenafil Normalizes Motility in Preclinical Models of Constipation. Gastroenterology. 2016 150(4):S697.

Shi L, Zhang W, Zou F, Mei L, Wu G, Teng Y. KLHL21, a novel gene that contributes to the progression of hepatocellular carcinoma. BMC Cancer. 2016 Oct 21;16(1):815.

Shonka DC Jr, Terris DJ. The American Thyroid Association Guidelines on Voice Assessment-Have We Done Enough? JAMA Otolaryngol Head Neck Surg. 2016 Feb 1;142(2):115-6. doi: 10.1001/ jamaoto.2015.3222. No abstract available.

Simon PS, Bardhan K, Chen MR, Paschall AV, Lu C, Bollag RJ, Kong FC, Jin J, Kong FM, Waller JL, Pollock RE, Liu K. NF-ÎşB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression. Oncotarget. 2016 Apr 26;7(17):23395415. doi: 10.18632/oncotarget.8246.

Simon RM, Howard LE, Freedland SJ, Aronson WJ, Terris MK, Kane CJ, Amling CL, Cooperberg MR, Vidal AC. Adverse pathology and undetectable ultrasensitive prostate-specific antigen after radical prostatectomy: is adjuvant radiation warranted? BJU Int. 2016 Jun;117(6):897-903. doi: 10.1111/bju.13182.

Simmerman EL, Thomson NB 3rd, Dillard TA, Hao Z, Sadek RF, Khleif SN, Schroeder C. Free Lung Cancer Screening Trends Toward a Twofold Increase in Lung Cancer Prevalence in the Underserved Southeastern United States. South Med J. 2017 Mar;110(3):188-194. doi: 10.14423/SMJ.0000000000000619.

Sivaprakasam S, Gurav A, Paschall AV, Coe GL, Chaudhary K, Cai Y, Kolhe R, Martin P, Browning D, Huang L, Shi H, Sifuentes H, Vijay-Kumar M, Thompson SA, Munn DH, Mellor A, McGaha TL, Shiao P, Cutler CW, Liu K, Ganapathy V, Li H, Singh N. An essential role of Ffar2 (Gpr43) in dietary fibre-mediated promotion of healthy composition of gut microbiota and suppression of intestinal carcinogenesis. Oncogenesis. 2016 Jun; 5(6): e238. doi: 10.1038/oncsis.2016.38.

Sivaprakasam S, Prasad PD, Singh N. Benefits of short-chain fatty acids and their receptors in inflammation and carcinogenesis. Pharmacol Ther. 2016 Aug;164:144-51. doi: 10.1016/j.pharmthera.2016.04.007.

Review.

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Solares CA, Mason E, Panizza BJ. Surgical Management of Perineural Spread of Head and Neck Cancers. J Neurol Surg B Skull Base. 2016 Apr;77(2):140-9. doi: 10.1055/s-0036-1579751.

Spassieva S, Bieberich E. Lysosphingolipids and sphingolipidoses: Psychosine in Krabbe's disease. J Neurosci Res. 2016 Nov;94(11):974-81. doi: 10.1002/jnr.23888. Review.

Spassieva SD, Ji X, Liu Y, Gable K, Bielawski J, Dunn TM, Bieberich E, Zhao L. Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency. Proc Natl Acad Sci U S A. 2016 May 24;113(21):5928-33. doi: 10.1073/pnas.1522071113.

Stansfield BK, Fain ME, Bhatia J, Gutin B, Nguyen JT, Pollock NK. Nonlinear Relationship between Birth Weight and Visceral Fat in Adolescents. J Pediatr. 2016 Jul;174:185-92. doi: 10.1016/j.jpeds.2016.04.012.

Sukumari-Ramesh S, Alleyne CH Jr, Dhandapani KM. The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Confers Acute Neuroprotection After Intracerebral Hemorrhage in Mice. Transl Stroke Res. 2016 Apr;7(2):141-8. doi: 10.1007/s12975-015-0421-y.

Sultan H, Fesenkova VI, Addis D, Fan AE, Kumai T, Wu J, Salazar AM, Celis E. Designing therapeutic cancer vaccines by mimicking viral infections. Cancer Immunol Immunother. 2016 Apr 6. [Epub ahead of print] Review. doi: 10.1007/s00262-016-1834-5.

Sun L, Burnett J, Gasparyan M, Xu F, Jiang H, Lin CC, Myers I, Korkaya H, Liu Y, Connarn J, He H, Zhang N, Wicha MS, Sun D. Novel cancer stem cell targets during epithelial to mesenchymal transition in PTENdeficient trastuzumab-resistant breast cancer. Oncotarget. 2016 Jun 6. doi: 10.18632/oncotarget.9839.

[Epub ahead of print] Sun X, Liu J, Xu C, Tang SC, Ren H. The insights of Let-7 miRNAs in oncogenesis and stem cell potency.

J Cell Mol Med. 2016 Sep;20(9):1779-88. doi: 10.1111/jcmm.12861. Review.

Sun ZZ, Zhang T, Ning K, Zhu R, Liu F, Tang SC, Jiang B, Hua D. B7-H3 upregulates BRCC3 expression, antagonizing DNA damage caused by 5-Fu. Oncol Rep. 2016 Jul;36(1):231-8. doi: 10.3892/or.2016.4808.

Suryawanshi A, Tadagavadi RK, Swafford D, Manicassamy S. Modulation of Inflammatory Responses by Wnt/β-Catenin Signaling in Dendritic Cells: A Novel Immunotherapy Target for Autoimmunity and Cancer.

Front Immunol. 2016 Oct 27;7:460. Review.

Teng Y, Bahassan A, Dong D, Hanold LE, Ren X, Kennedy EJ, Cowell JK. Targeting the WASF3-CYFIP1 Complex Using Stapled Peptides Suppresses Cancer Cell Invasion. Cancer Res. 2016 Feb 15;76(4):96573. doi: 10.1158/0008-5472.CAN-15-1680.

Teng Y, Qin H, Bahassan A, Bendzunas NG, Kennedy EJ, Cowell JK. The WASF3-NCKAP1-CYFIP1 Complex Is Essential for Breast Cancer Metastasis. Cancer Res. 2016 Sep 1;76(17):5133-42. doi: 10.1158/0008-5472.CAN-16-0562.

Teng Y, Ren X, Li H, Shull A, Kim J, Cowell JK. Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis-promoting protein. Oncogene. 2016 Jan 21;35(3):333-34. doi: 10.1038/ onc.2015.86 Teng Y, Pi W, Wang Y, Cowell JK. WASF3 provides the conduit to facilitate invasion and metastasis in breast cancer cells through HER2/HER3 signaling. Oncogene. 2016 Sep 1; 35(35): 4633-40. doi: 10.1038/onc.2015.527

Georgia Cancer Center 2016 Publications

Spellman A, Tang SC. Immunotherapy for breast cancer: past, present, and future. Cancer Metastasis Rev. 2016 Dec;35(4):525-546. doi: 10.1007/s10555-016-9654-9.

Terris DJ. Continuous Vagal Nerve Monitoring: Too Much of a Good Thing? World J Surg. 2016 Mar;40 (3):681-2. doi: 10.1007/s00268-016-3406-4. No abstract available.

Terris DJ, Chaung K, Duke WS. Mounting Evidence of the Potential Perils Associated with Continuous Intraoperative Neuromonitoring: Reply. World J Surg. 2016 Mar;40(3):770-1. doi: 10.1007/s00268-0153384-y. No abstract available.

Terris DJ, Stack BC Jr. Parathyroid Surgery: Getting It Right the First Time. Otolaryngol Head Neck Surg.

2016 Feb;154(2):396. doi: 10.1177/0194599815619601. No abstract available.

Thomson NB 3rd, Rawson JV, Slade CP, Bledsoe M. Transformation and Transformational Leadership:: A Review of the Current and Relevant Literature for Academic Radiologists. Acad Radiol. 2016 May;23 (5):592-9. doi: 10.1016/j.acra.2016.01.010. Review.

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Törn C, Liu X, Hagopian W, Lernmark Å, Simell O, Rewers M, Ziegler AG, Schatz D, Akolkar B, OnengutGumuscu S, Chen WM, Toppari J, Mykkänen J, Ilonen J, Rich SS, She JX, Sharma A, Steck A, Krischer J; TEDDY Study Group. Complement gene variants in relation to autoantibodies to beta cell specific antigens and type 1 diabetes in the TEDDY Study. Sci Rep. 2016 Jun 16;6:27887. doi: 10.1038/srep27887.

Georgia Cancer Center 2016 Publications

Tsai YY, Rainey WE, Johnson MH, Bollag WB. VLDL-activated cell signaling pathways that stimulate adrenal cell aldosterone production. Mol Cell Endocrinol. 2016 Sep 15;433:138-46. doi: 10.1016/ j.mce.2016.05.018.

Uusitalo U, Liu X, Yang J, Aronsson CA, Hummel S, Butterworth M, Lernmark Å, Rewers M, Hagopian W, She JX, Simell O, Toppari J, Ziegler AG, Akolkar B, Krischer J, Norris JM, Virtanen SM; TEDDY Study Group. Association of Early Exposure of Probiotics and Islet Autoimmunity in the TEDDY Study. JAMA Pediatr. 2016 Jan 1;170(1):20-8. doi: 10.1001/jamapediatrics.2015.2757.

Vaughan CA, Pearsall I, Singh S, Windle B, Deb SP, Grossman SR, Yeudall WA, Deb S. Addiction of lung cancer cells to GOF p53 is promoted by up-regulation of epidermal growth factor receptor through multiple contacts with p53 transactivation domain and promoter. Oncotarget. 2016 Mar 15;7(11):12426-46. doi: 10.18632/oncotarget.6998.

Vehik K, Lynch KF, Schatz DA, Akolkar B, Hagopian W, Rewers M, She JX, Simell O, Toppari J, Ziegler AG, Lernmark Å, Bonifacio E, Krischer JP; TEDDY Study Group. Reversion of β-Cell Autoimmunity Changes Risk of Type 1 Diabetes: TEDDY Study. Diabetes Care. 2016 Sep;39(9):1535-42. doi: 10.2337/dc160181.

Wang GD, Nguyen HT, Chen H, Cox PB, Wang L, Nagata K, Hao Z, Wang A, Li Z, Xie J. X-Ray Induced Photodynamic Therapy: A Combination of Radiotherapy and Photodynamic Therapy. Theranostics. 2016 Oct 1;6(13):2295-2305.

Wang R, Islam BN, Bridges A, Sharman SK, Hu M, Hou Y, Somanath PR, Venable L, Singh N, Kim S, Sridhar S, Hofmann F, Browning DD. cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O 3a in the Colon Epithelium. Am J Pathol. 2017 Feb:187(2), 377–389.

Wang S, Dong Z. Environmental hit on a genetic basis in polycystic kidney disease. Am J Physiol Renal Physiol. 2016 Dec 1;311(6):F1358-F1359. doi: 10.1152/ajprenal.00452.2016. No abstract available. doi: 10.1016/j.ajpath.2016.10.016.

Wang X, Cao Q, Yu L, Shi H, Xue B, Shi H. Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity. JCI Insight. 2016 Nov 17;1(19):e87748 Wang Y, Jadhav RR, Liu J, Wilson D, Chen Y, Thompson IM, Troyer DA, Hernandez J, Shi H, Leach RJ, Huang TH, Jin VX. Roles of Distal and Genic Methylation in the Development of Prostate Tumorigenesis Revealed by Genome-wide DNA Methylation Analysis. Sci Rep. 2016 Feb 29;6:22051. doi: 10.1038/ srep22051.

Wang Y, Liu T, Xu D, Shi H, Zhang C, Mo YY, Wang Z. Predicting DNA Methylation State of CpG Dinucleotide Using Genome Topological Features and Deep Networks. Sci Rep. 2016 Jan 22;6:19598. doi: 10.1038/srep19598.

Ward CM, Li B, Pace BS. Stable expression of miR-34a mediates fetal hemoglobin induction in K562 cells.

Exp Biol Med (Maywood). 2016 Mar 2. pii: 1535370216636725. [Epub ahead of print] Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, Odame I, Fuh B, George A, Owen W, Luchtman-Jones L, Rogers ZR, Hilliard L, Gauger C, Piccone C, Lee MT, Kwiatkowski JL, Jackson S, Miller ST, Roberts C, Heeney MM, Kalfa TA, Nelson S, Imran H, Nottage K, Alvarez O, Rhodes M, Thompson AA, Rothman JA, Helton KJ, Roberts D, Coleman J, Bonner MJ, Kutlar A, Patel N, Wood J, Piller L, Wei P, Luden J, Mortier NA, Stuber SE, Luban NL, Cohen AR, Pressel S, Adams RJ. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, noninferiority trial. Lancet. 2016 Feb 13;387(10019):661-70. doi: 10.1016/S0140-6736(15)01041-7.

Whitney CA, Howard LE, Amling CL, Aronson WJ, Cooperberg MR, Kane CJ, Terris MK, Freedland SJ. Race does not predict the development of metastases in men with nonmetastatic castration-resistant prostate cancer. Cancer. 2016 Dec 15;122(24):3848-3855. doi: 10.1002/cncr.30221.

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Williams LB, Franklin B, Evans MB, Jackson C, Hill A, Minor M. Turn the Beat Around: A Stroke Prevention Program for African-American Churches. Public Health Nurs. 2016 Jan;33(1):11-20. doi: 10.1111/ phn.12234.

Wu J, Xu X, Lee EJ, Shull AY, Pei L, Awan F, Wang X, Choi JH, Deng L, Xin HB, Zhong W, Liang J, Miao Y, Wu Y, Fan L, Li J, Xu W, Shi H. Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming. Oncotarget. 2016 Jun 28;7(26):40558-40570. doi: 10.18632/ oncotarget.9941.

Xiao L, Xu X, Zhang F, Wang M, Xu Y, Tang D, Wang J, Qin Y, Liu Y, Tang C, He L, Greka A, Zhou Z, Liu F, Dong Z, Sun L. The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1. Redox Biol. 2016 Dec 21;11:297-311. doi: 10.1016/ j.redox.2016.12.022. [Epub ahead of print] Xie D, Bollag WB. Obesity, hypertension and aldosterone: is leptin the link? J Endocrinol. 2016 Jul;230 (1):F7-F11. doi: 10.1530/JOE-16-0160. Review.

Xie X, Gao L, Shull AY, Teng Y. Stapled peptides: providing the best of both worlds in drug development.

Future Med Chem. 2016 Oct;8(16):1969-1980.

Xie X, Tang SC, Cai Y, Pi W, Deng L, Wu G, Chavanieu A, Teng Y. Suppression of breast cancer metastasis through the inactivation of ADP-ribosylation factor 1. Oncotarget. 2016 Sep 6;7(36): 58111-58120. doi: 10.18632/oncotarget.11185. [Epub ahead of print] Xuan F, Huang M, Liu W, Ding H, Yang L, Cui H. Homeobox C9 suppresses Beclin1-mediated autophagy in glioblastoma by directly inhibiting the transcription of death-associated protein kinase 1. Neuro Oncol. 2016 Jun;18(6):819-29. doi: 10.1093/neuonc/nov281.

Yang J, Lynch KF, Uusitalo UM, Foterek K, Hummel S, Silvis K, AndrĂŠn Aronsson C, Riikonen A, Rewers M, She JX, Ziegler AG, Simell OG, Toppari J, Hagopian WA, Lernmark Ă&#x2026;, Akolkar B, Krischer JP, Norris JM, Virtanen SM, Johnson SB; TEDDY Study Group. Factors associated with longitudinal food record compliance in a paediatric cohort study. Public Health Nutr. 2016 Apr;19(5):804-13. doi: 10.1017/ S1368980015001883.

Yang Z, Peng M, Cheng L, Jones K, Maihle NJ, Mivechi NF, Ko L. GT198 Expression Defines Mutant Tumor Stroma in Human Breast Cancer. Am J Pathol. 2016 May;186(5):1340-50. doi: 10.1016/ j.ajpath.2016.01.006.

Young P, Homlar KC. Extreme Postinjection Flare in Response to Intra-Articular Triamcinolone Acetonide (Kenalog). Am J Orthop (Belle Mead NJ). 2016 Mar-Apr;45(3):E108-11.

Yowtak J, Sharma S, Forseen SE, Alleyne CH Jr. Anterior gray matter pituicytic heterotopia with monomorphic anterior pituitary cells: A variant of non-secretory pituitary adenoma neuronal choristoma (PANCH)?

Report of a rare case and review of literature. World Neurosurg. 2016 Oct 12. pii: S1878-8750(16)30983-4. doi: 10.1016/j.wneu.2016.09.125.

Xu L, Kittrell S, Yeudall WA, Yang H. Folic acid-decorated polyamidoamine dendrimer mediates selective uptake and high expression of genes in head and neck cancer cells. Nanomedicine (Lond). 2016 Nov;11 (22):2959-2973.

Georgia Cancer Center 2016 Publications

Wu Q, Bhole A, Qin H, Karp J, Malek S, Cowell JK, Ren M. SCLLTargeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models. Oncotarget. 2016 Aug 2;7(31):49733-49742. doi: 10.18632/oncotarget.10438.

Yu RK, Usuki S, Itokazu Y, Wu HC. Novel GM1 ganglioside-like peptide mimics prevent the association of cholera toxin to human intestinal epithelial cells in vitro. Glycobiology. 2016 Jan;26(1):63-73. doi: 10.1093/ glycob/cwv080.

Zakharia Y, Munn D, Link C, Vahanian N, Kennedy E. ACTR-53. Interim analysis of phase 1B/2 combination study of the IDO pathway inhibitor indoximod with temozolomide for adult patients with temozolomiderefractory primary malignant brain tumors. Neuro Oncol. 2016 18 (suppl 6):vi13-vi14. doi: 10.1093/neuonc/ now212.051.

Zdanov S, Mandapathil M, Abu Eid R, Adamson-Fadeyi S, Wilson W, Qian J, Carnie A, Tarasova N, Mkrtichyan M, Berzofsky JA, Whiteside TL, Khleif SN. Mutant KRAS Conversion of Conventional T Cells into Regulatory T Cells. Cancer Immunol Res. 2016 Apr;4(4):354-65. doi: 10.1158/2326-6066.CIR-15-0241.

Zhang H, Kong V, Huang K, Jin JY. Correction of Bowtie-Filter Normalization and Crescent Artifacts for a Clinical CBCT System. Technol Cancer Res Treat. 2016 Feb 1. pii: 1533034615627584. [Epub ahead of print]

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Zhang H, Ren L, Kong V, Giles W, Zhang Y, Jin JY. An interprojection sensor fusion approach to estimate blocked projection signal in synchronized moving grid-based CBCT system. Med Phys. 2016 Jan;43 (1):268. doi: 10.1118/1.4937934.

Zhang L, Varma NR, Gang ZZ, Ewing JR, Arbab AS, Ali MM. Targeting Triple Negative Breast Cancer with a Small-sized Paramagnetic Nanoparticle. J Nanomed Nanotechnol. 2016 Oct;7(5). pii: 404. doi: 10.4172/2157-7439.1000404.

Georgia Cancer Center 2016 Publications

Zhang M, Davis JE, Li C, Gao J, Huang W, Lambert NA, Terry AV Jr, Wu G. GGA3 interacts with a G protein-coupled receptor and modulates its cell surface export. Mol Cell Biol. 2016 Jan 25;36(7):1152-63. doi: 10.1128/MCB.00009-16.

Zhang M, Huang W, Gao J, Terry AV, Wu G. Regulation of Îą2B-Adrenergic Receptor Cell Surface Transport by GGA1 and GGA2. Sci Rep. 2016 Nov 30;6:37921. doi: 10.1038/srep37921.

Zhang Y, Lai J, Du Z, Gao J, Yang S, Gorityala S, Xiong X, Deng O, Ma Z, Yan C, Susana G, Xu Y, Zhang J. Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress. Oncotarget. 2016 May 4. doi: 10.18632/oncotarget.9156. [Epub ahead of print] Zhao E, Ding J, Xia Y, Liu M, Ye B, Choi JH, Yan C, Dong Z, Huang S, Zha Y, Yang L, Cui H, Ding HF. KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism. Cell Rep. 2016 Jan 26;14(3):506-19. doi: 10.1016/j.celrep.2015.12.053.

Zhao J, Li X, Guo M, Yu J, Yan C. The common stress responsive transcription factor ATF3 binds genomic sites enriched with p300 and H3K27ac for transcriptional regulation. BMC Genomics. 2016 May 4;17 (1):335. doi: 10.1186/s12864-016-2664-8.

Zhao J, Xia Y, Kaminski J, Hao Z, Mott F, Campbell J, Sadek R, Kong FM. Treatment-Related Death during Concurrent Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Studies. PLoS One. 2016 Jun 14;11(6):e0157455. doi: 10.1371/journal.pone.0157455. eCollection 2016.

Zhao Z, Reinstatler L, Klaassen Z, Xu Y, Yang X, Madi R, Terris MK, Qian SY, Kelavkar U, Moses KA. The Association of Fatty Acid Levels and Gleason Grade among Men Undergoing Radical Prostatectomy.

PLoS One. 2016 Nov 23;11(11):e0166594. doi: 10.1371/journal.pone.0166594.

Zhong H, Davis A, Ouzounova M, Carrasco RA, Chen C, Breen S, Chang YS, Huang J, Liu Z, Yao Y, Hurt E, Moisan J, Fung M, Tice DA, Clouthier SG, Xiao Z, Wicha MS, Korkaya H, Hollingsworth RE. A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors.

Cancer Res. 2016 Jan 15;76(2):480-90. doi: 10.1158/0008-5472.CAN-15-0883.

Zhong T, Men Y, Lu L, Geng T, Zhou J, Mitsuhashi A, Shozu M, Maihle NJ, Carmichael GG, Taylor HS, Huang Y. Metformin alters DNA methylation genome-wide via the H19/SAHH axis. Oncogene. 2016 Oct 24. doi: 10.1038/onc.2016.391. [Epub ahead of print] Zhong X, Zhao E, Tang C, Zhang W, Tan J, Dong Z, Ding HF, Cui H. Antibiotic drug tigecycline reduces neuroblastoma cells proliferation by inhibiting Akt activation in vitro and in vivo. Tumour Biol. 2016 Jun;37 (6):7615-23. doi: 10.1007/s13277-015-4613-6.

Zhou HM, Fang YY, Weinberger PM, Ding LL, Cowell JK, Hudson FZ, Ren M, Lee JR, Chen QK, Su H, Dynan WS, Lin Y. Transgelin increases metastatic potential of colorectal cancer cells in vivo and alters expression of genes involved in cell motility. BMC Cancer. 2016 Feb 4;16(1):55. doi: 10.1186/s12885-0162105-8.

Zhu H, Bhagatwala J, Huang Y, Pollock NK, Parikh S, Raed A, Gutin B, Harshfield GA, Dong Y. Race/ Ethnicity-Specific Association of Vitamin D and Global DNA Methylation: Cross-Sectional and Interventional Findings. PLoS One. 2016 Apr 6;11(4):e0152849. doi: 10.1371/journal.pone.0152849. eCollection 2016.

Zumsteg ZS, Chen Z, Howard LE, Amling CL, Aronson WJ, Cooperberg MR, Kane CJ, Terris MK, Spratt DE, Sandler HM, Freedland SJ. Number of Unfavorable Intermediate-Risk Factors Predicts Pathologic Upstaging and Prostate Cancer-Specific Mortality Following Radical Prostatectomy: Results From the SEARCH Database. Prostate. 2016 Sep 29. doi: 10.1002/pros.23255. [Epub ahead of print]

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