Center for Medical Genetics and Genomics

ChristianaCare’s Center for Medical Genetics and Genomics is transforming how we treat cancer

From left: Bruce Boman, M.D., Ph.D., MS, FACP, Amanda Peraino, LCGC, Zohra Ali-Khan Catts, LCGC, Kara Morrison, LCGC, Nicole Lester, LCGC, Kendra Flores, LCGC, Pawel Pomianowski, M.D.

Advancing precision medicine by looking at what’s in our genes

ChristianaCare’s Center for Medical Genetics and Genomics, under the direction of Pawel T. Pomianowski, M.D., at the Helen F. Graham Cancer Center & Research Institute is leveraging what we know about the human genome and disease to change the way we predict, diagnose and treat cancer more precisely and personally than ever before.

Within the Center, the Genetic Risk Assessment Program offers consultation, genetic testing and support for families who may have a hereditary risk for certain cancers as well as other diseases. The program is one of only three such statewide programs in the United States that documents cancer risks that run in families.

“At ChristianaCare, we are unique among many institutions with our focus on both clinical genetics and genomics to help guide the care of our patients,” said Dr. Pomianowski, who specializes in clinical genetics and internal medicine. “This is a fundamentally different approach from other institutions in our area that are primarily research based and where clinical genetics often takes a back seat.”

Finding out what’s in our genes

What we know about our genes at work and how they interact with each other and our environment is changing how we treat some cancers. At the Graham Cancer Center, clinicians have next generation sequencing capability (tumor profiling) to examine the noninherited genetic characteristics of a patient’s tumor and to use this information to plan what treatment would work best.

Another layer of information can come from germline genetic testing. When appropriate, clinicians can examine germline gene changes, those inherited and passed down through generations, to help guide individualized treatment decisions.

“Next generation sequencing technology allows us to look at individual rare variants or gene alterations that play a significant role in cancer development,” said Dr. Pomianowski.

“In this way we can design a specific cancer treatment plan for each individual patient, and predict cancer risks for other members of the family who may still be cancer free.” For these family members, genetic counseling about cancer risk factors and appropriate interventions can help minimize the chances that they too might eventually develop disease.

The Center maintains a statewide High-Risk Familial Cancer Registry of some 13,988 individuals from Delaware and surrounding communities whose family histories in some cases extend back generations.

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Patients who participate in the genetic counseling program can have their family history data entered into the registry to help scientists learn more about cancer patterns in our community and work toward new discoveries in cancer prevention, diagnosis and treatment. The team is also building similar registries for cardiovascular and adult-onset neurological diseases. Dr. Pomianowski has more than 12 years of hospital and clinical practice experience that includes establishing one of only two genetic counseling and risk assessment programs for U.S. veterans on the East Coast.

“The Center for Medical Genetics and Genomics, under Dr. Pomianowski’s direction, is a key component of our comprehensive cancer program serving our community and our region,” said Nicholas Petrelli, M.D., Bank of America endowed medical director of the Helen F. Graham Cancer Center & Research Institute. “Today, by integrating the science into individualized treatment planning, we are opening the door wider to more precisely targeted and potentially more effective therapies, even for some cancers where there are few current treatment options.”

Documenting Delaware’s unique genetic footprint

Beyond looking at panels of known diseaseassociated genes, the team is working on developing an in-house genomics program where in the very near future, clinicians will be sequencing and interpreting the entire genome of an individual patient. “The future of precision medicine,” Dr. Pomianowski said, “lies in our ability to read a patient’s entire set of genes, their genome, and to target how we care for that patient based on his or her own unique genomic makeup.

“This approach has shown clinical utility and financial viability at select institutions elsewhere in the country and would bring significant gains for our patients in Delaware and the region,” he said.

Whole genome sequencing would allow for relevant genes to be sequenced based on individual cases without limitations posed by what might be considered the “established gene panels” available commercially.

Dr. Pomianowski points out that whole genome sequencing would also allow geneticists to take another look at a person’s genome, perhaps stored as part of their electronic medical record, when new information becomes available and new disease-causing genes are identified. The number of diseases known to have a genetic basis is increasing rapidly. So too is our knowledge of genomic variants or gene changes, which may occur at different rates within a population and individually or collectively could affect a person’s risk for disease. This risk is tabulated as a person’s “polygenic risk score.”

“Having a whole genome sequencing program at our institution will allow us to interpret patient genomes for common variants with small effects that are the basis of polygenic risk scores,” Dr. Pomianowski said. “These risk scores, although not ready

for prime time yet, are right around the corner for more widespread use in both cancer and cardiovascular genetics.” Some variants are rare in one region of the globe and are common in others. “An in-house genomic database would be a genetic map of ChristianaCare’s unique patient community,” he said.

Pharmacogenetics for more personalized medicine

Genomic profiling also offers clues to how a patient might respond to different drugs and which ones might be harmful.

“Not all medicines work the same or have the same response from every patient, particularly those who have undergone prior cancer treatments,” said Dr. Pomianowski.

“That is why at ChristianaCare, we are poised to implement a pharmacogenetics program. Our plan is to have an onsite pharmacist who is trained to evaluate our patients based on their unique genomic profiles. This way, we can optimize the benefits of a prescribed drug while minimizing any negative or adverse side effects,” he said.

At the Graham Cancer Center, medical geneticists and certified genetic counselors work collaboratively with multidisciplinary teams of experts (oncologists, cardiologists and radiologists, among others) throughout the health system.

One example is a multidisciplinary clinic where specialists collaborate to improve outcomes for patients with amyloidosis. This is a rare condition that occurs when an abnormal protein, called the amyloid protein, builds up and affects normal organ function. Some forms of this disease are hereditary. Successful treatment is heavily dependent on accurate characterization (including genetics) of the amyloid protein.

The Center continues to expand genetic counseling and risk assessment services in cancer genetics while transitioning to an essential service across many specialties, including hereditary cardiovascular disease, adult-onset and childhood-onset hereditary syndromes, genetic neurological disease and prenatal risk assessment and counseling.

“Nowadays, every oncologist should be using the tools available through medical genetics and genomics, otherwise they are not optimally helping their patients,” said Dr. Pomianowski. “However, these tools are not being used as well in other disease areas where medical evidence has shown they have potential benefit. At ChristianaCare we are working to change that.”

Jennifer Sims Mourtada, Ph.D.

First-of-its-kind study in Delaware looks for risk factors linked to aggressive breast cancer in both biology and environment

Historic partnership with the Wistar Institute facilitates a novel multilevel and multidisciplinary approach

Adecade-long partnership between clinician scientists at the Helen F. Graham Cancer Center & Research Institute and the Wistar Institute of Philadelphia has produced a new and unique opportunity to examine risk factors linked to triple negative breast cancer (TNBC) in Delaware neighborhoods. The multilevel study is the first of its kind in Delaware and among only a few in the nation to examine a person’s biological cancer risk factors in the context of the neighborhood in which she lives. Another unique aspect is the multidisciplinary team itself.

ChristianaCare lead scientists are Director of Population Health Research Scott

Siegel, Ph.D., MHCDS, who is also a member of the ChristianaCare Institute for Research on Equity and Community Health, and Lead Research Scientist Jennifer Sims-Mourtada, Ph.D., at the Graham Center’s Cawley Center for Translational Cancer Research (CTCR). They are joined by Zachary Schug, Ph.D., assistant professor at the Wistar Institute Ellen and Ronald Caplan Cancer Center’s Molecular and Cellular Oncogenesis Program. “There are many risk factors for breast cancer that can be modified, such as diet, exercise and alcohol consumption,” Dr. Sims-Mourtada said. “If we can find a biomarker to identify someone at higher risk, we can modify those risk factors and potentially prevent or alter the course of this disease.”

Dr. Sims-Mourtada’s research interests include the effects of inflammation and alcohol metabolism on breast cancer. Although it is not widely known, alcohol is an established risk factor for breast cancer.

Dr. Sims-Mourtada is particularly interested in the actions of an alcohol enzyme called ALDH (alcohol dehydrogenase) that plays an important role in breaking down alcohol molecules and eliminating them from the body.

“ALDH is over-expressed in breast tumors and has been associated with poor outcomes,” said Dr. Sims-Mourtada. “I am very interested in the function of this enzyme and its role in tumor growth.” Up till now, her research has focused on tumor biology and genetics, but Dr. Sims-

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Mourtada says the new study takes a broader systemic approach.

‘This time, we are looking at the whole person, not only what is happening inside her body, but also how that correlates with what is happening outside in her environment,” she said. “We are asking questions like what she is eating and drinking, and how that is affected by where she lives and what is happening in her community.”

Delaware ideal for study

Delaware ranks highest in the nation for the incidence of TNBC, an aggressive form that affects African American women at twice the rate of white women with poorer outcomes. Delaware also has the highest rate of alcohol-attributable breast cancers.

In this study, the researchers are looking at potential contributing factors such as diet and alcohol use, along with genetic variants and the effects of these on cancer metabolism among women in Delaware and surrounding areas.

“Our large and diverse patient population makes the Graham Cancer Center ideal for this kind of study,” Dr. Siegel said.

The Graham Cancer Center provides care to some 600 patients annually, which account for about 85% of the total cases from New Castle County.

Looking at patient records over an eightyear period from the Graham Cancer Center registry, the team identified clusters of high TNBC incidence in two distinct areas of New Castle County. “Once we found hot spots we began to look at both clinical and demographic factors among the women in these areas, including obesity and unhealthy alcohol use as well as neighborhood characteristics such as the number of alcohol retailers or limited options to purchase healthy foods,” Dr. Siegel said.

“We know that Black women are at increased risk for developing TNBC but the risk is also increased for both white and Black women who live in certain neighborhoods,” he said. “Our findings so far provide even stronger evidence that neighborhood and environment may be contributing to that risk.” The team published results of their initial population health assessment in Cancer Epidemiology, Biomarkers & Prevention in January 2022.

Multimillion-dollar next phase in the works

They plan to pursue grant funding to support what promises to be a multimillion-dollar study to continue over the next several years. The next phase of the study will add a

Scott Siegel, Ph.D., MHCDS

human tissue component to support the research of both Dr. Sims-Mourtada and Dr. Schug with samples provided through the Graham Cancer Center’s Tissue Procurement program.

“I think the multilevel approach we are taking with this type of socio-biological analysis is extremely unique,” said Dr. Schug. “We each have our expertise and by combining our knowledge we can achieve something not one of us could have achieved on our own. This is where science needs to go.”

Dr. Schug’s expertise at Wistar is in cancer metabolism. He uses a technology called mass spectrometry to analyze blood plasma for metabolites and lipids that could potentially be biomarkers for advanced breast cancer.

“Partnerships like ours with the Graham Cancer Center are extremely important if we want to have access to patient samples, not only for my work but for the entire institute,” Dr. Schug said. Using machine-learning software the team continues to analyze their collective data to draw relationships between identified cancer hot spots and modifiable risk factors.

“We might identify a patient with a high amount of a certain metabolite in their blood, for example, that strongly correlates with their alcohol drinking pattern, which in turn could be driven by how closely they live to an alcohol retailer,” Dr. Schug said.

“In addition, we can examine whether that person has a genetic mutation in their DNA that could contribute to how their body metabolizes alcohol. From that we can try to determine if by-products of that metabolism are potentially tumor causing, and whether they are contributing to her advanced breast cancer.”

Locating communities at risk

Community outreach and collaboration have long been a priority for the Graham Cancer Center and that includes targeted programs in underserved neighborhoods to spread the word about the risk factors and prevention for TNBC. Those efforts will be supported and informed by ongoing study findings.

“What we are very interested in is looking at how these data we are collecting can help women now,” said Dr. Siegel.

“As we continue our study, we are looking closer at the communities where we see the highest level of risk, and expanding relationships with various stakeholders to improve cancer prevention and control,” he said.

“In a lot of ways our community is representative of the country’s demographics, which could make our findings of interest to other places well beyond our own local area.”

Zachary Schug, Ph.D.

News briefs

Research shows good news for cancer treatments that will use CRISPR gene editing

A new study from scientists at ChristianaCare’s Gene Editing Institute is advancing the safety and efficacy of using CRISPR gene editing in patient treatments by demonstrating how to identify and evaluate the broad-based biological impact of gene editing on targeted tissues, where the edits are designed to fully disable or “knock out” a specific sequence of genetic code.

The work, published in the Nature journal Gene Therapy, supports the institute’s efforts to improve lung cancer treatments by using CRISPR to disable or alter a master regulator gene to prevent it from producing a protein that blunts the impact of chemotherapy. The lead author on the article was Kelly Banas, Ph.D., principal investigator and leader of the Oncology Group. “We found that when you use CRISPR, the edits sometimes end up altering rather than completely disabling the target gene, so we developed a process to gain a more complete understanding of what that means for patients,” said Eric Kmiec, Ph.D., executive director and chief scientific officer of ChristianaCare’s Gene Editing Kelly Banas, Ph.D. Institute and the principal author of the study. Dr. Kmiec said that for his team’s lung cancer work, “We discovered that even when our CRISPR-based genetic manipulation did not completely disable the targeted gene, it altered it in ways that that appear to make lung cancer tumors more sensitive to chemotherapy. “We were fortunate that our strategy for using CRISPR to improve lung cancer treatments has been validated once again,” he added. “But our commitment to conducting an unbiased assessment of our approach highlights the importance of examining all potential outcomes of an attempt to use CRISPR to knock out

Eric Kmiec, Ph.D.

a specific gene. Specifically, anyone developing CRISPR therapies needs to be on the lookout for edits that don’t fully knock out a section of DNA code—and evaluate the potential impacts for patients. They could be positive, as they were in our case, negative or neutral, but they need to be known.”

ChristianaCare and Wistar Institute advance partnership with new cancer research strategies plus focus on “mini organs” to revolutionize search for biomarkers and drug targets

ChristianaCare’s Helen F. Graham Cancer Center & Research Institute is advancing its historic partnership with the Ellen and Ronald Caplan Cancer Center of the Wistar Institute in Philadelphia with three new research projects under way. The new research projects consist of a population health study targeting the high incidence of triple negative breast cancer. Other projects focus on a new therapeutic target for epithelial ovarian cancer, the most lethal gynecologic cancer in the developed world and the development of “mini organs” derived from stem cells. The Graham Cancer Center made history when it signed a first-of-its-kind agreement in 2011 with the Wistar Institute, pairing a National Cancer Institute, NCI-designated basic research institution with a community cancer center that is also an NCI Community Oncology Research Program (NCORP).

“Our partnership with Wistar has attracted national recognition as a model of collaboration that leverages cutting-edge research to benefit cancer prevention and therapy statewide,” says Nicholas J. Petrelli, M.D., Bank of America endowed medical director of the Helen F. Graham Cancer Center & Research Institute. “With Wistar, our productive collaborations over the last decade continue to drive discovery research toward clinical trials to benefit patients here at the Graham Cancer Center and in communities everywhere.”

These images show before and after CRISPR-directed gene editing of the NRF2 gene in lung cancer cells.

News briefs

ChristianaCare establishes first translational cancer research postdoctoral fellowship at the Helen F. Graham Cancer Center & Research Institute

Lead Scientist Jennifer Sims-Mourtada, Ph.D., director of the Breast Translational Cancer Research Program at the Cawley Center for Translational Cancer Research (CTCR), has received $1,160,681 from the Lisa Dean Moseley Foundation to establish a first-of-its-kind translational cancer research fellowship at ChristianaCare’s Helen F. Graham Cancer Center & Research Institute.

The five-year grant expands current research partnerships with the Moseley Foundation by providing fellowships to support one to two fellows per year. The fellowship will broaden Cawley CTCR training opportunities for early career Ph.D.s and physician scientists in academic medicine or translational cancer research with a major focus on cancer stem cells.

Inaugural Walk/Run for the Lung supports lung cancer technology

More than 550 people participated in the Friends of the Helen F. Graham Cancer Center & Research Institute’s inaugural 5K Walk/Run for the Lung on April 30. The event raised nearly $200,000 to support the purchase of a leading-edge robotic-assisted bronchoscopy platform that enables earlier and more accurate diagnosis of small and hard-to-reach nodules in the periphery of the lung. Dan and Susan Katzin of Greenville generously pledged to match up to $375,000 for the technology platform.

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Cancer Update is produced by the ChristianaCare Department of External Affairs. Email us at editor@christianacare.org with questions or comments. © ChristianaCare. All rights reserved.

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