On Target by The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

ontarget KIMMEL CANCER CENTER

letter from the chairman

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A publication by the Department of Radiation Oncology and Molecular Radiation Sciences of The Johns Hopkins School of Medicine Winter 2009 • Volume II , Number 1

Cancer Treatment Heats Up

Welcome Back, Colleagues and Friends of Radiation Oncology We are pleased to present our second issue of On Target, the newsletter of the Department of Radiation Oncology and Molecular Radiation Sciences. In this issue, we introduce you to four more of our stellar researchers, whose cutting-edge work exemplifies our mission of accelerating the research and delivery of novel cancer treatments to improve the lives of our patients. These brilliant and dedicated researchers, and the other equally talented members of this department, are taking cancer research and patient care to new levels of excellence. Through our newsletter, we again invite you to learn more about our lifesaving and life-changing discoveries. From groundbreaking clinical trials to the latest technology, we are continually in search of the best and most innovative ways to treat our patients. This is our goal and guides all that we do. The faculty and I thank you for partnering with us and for helping us to realize this goal.

Sincerely, Theodore L. DeWeese, M.D. Chairman, Department of Radiation Oncology and Molecular Radiation Sciences The Johns Hopkins School of Medicine

Dr. Robert Ivkov uses heated iron oxide nanoparticles to fight cancer.

eet Robert Ivkov, Ph.D., visiting assistant professor in the Division of Molecular Radiation Sciences of the Department of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins. With a background in physical chemistry and materials science, he is an expert in the field of nanoparticles, with a particular interest in magnetic nanoparticles. He brings his unique talents to the multidisciplinary team that makes Radiation Oncology and Molecular Radiation Sciences outstanding in the field of cancer research and treatment. Dr. Ivkov’s work builds on previous re-

search, which has shown that heat sensitizes cancer cells, making them easier targets for chemotherapy and radiation. Until now, applying this knowledge to create successful treatment options for patients has been difficult. The difficulty has been largely a technical challenge: how to heat cancerous tissue without harming healthy tissue, and how accurately to measure how much heat is absorbed by the cancer. If a doctor is unable to deliver heat selectively to the cancer or to know precisely how much heat is absorbed by the cancer, it is very difficult to provide treatment plans that will produce consistent and predictable results for the patient. (continued on page 2)

ON TARGET • winter 2009

Cancer Treatment Heats Up (continued from page 1)

the Goal: heating iron oxide nanoparticles introduced into tumors to make the cancer cells more susceptible to chemotherapy and radiation.

In general, cancer cells are particularly susceptible to changes in temperature. Increasing the temperature of a cancer cell from 37°C to 43°C for a sufficient period of time can make the cancer very sensitive to radiation or chemotherapy. This represents a very exciting opportunity to make already effective treatments even more effective and, potentially, less likely to produce unwanted side effects. Dr. Ivkov and his team are now showing that they can cause cancer-specific heating by putting magnetic nanoparticles into the cancer and exposing these nanoparticlecontaining cancers to an alternating magnetic field, which heats the particles. The magnetic nanoparticles can either be injected directly into the cancerous tissue, or, can accumulate in the cancer, after intravenous injection, if they have first been coated with suitable targeting molecules that take them directly to cancer cells. In this manner, the cancer is treated locally, at the cellular level, and, by targeting the nanoparticles only to cancer cells, the damage to healthy tissue is minimized. In some of his early work, Dr. Ivkov used sugar polymer-coated nanoparticles that contained small amounts of iron oxide crystals. The sugar polymer coating was chosen to allow the nanoparticles to circulate quickly through the bloodstream to the cancer. About two or three days after injection into mice with human breast tumor xenografts, Dr. Ivkov applied the alternating magnetic field, which heated the iron oxide, which, in turn, raised the temperature inside the cancer cells. Dr. Ivkov observed that this increased temperature was enough to reduce tumor growth. He posits that the higher temperature should make the tumors “exquisitely susceptible to chemotherapy and radiation,” without causing significant side effects in the mice. Dr. Ivkov chooses to explore iron oxide because it is ubiquitous in nature, being found in both migratory birds and humans, and because it may be the lowest risk to patients of all the possible nanoparticle materials that can be injected. As Dr. Ivkov points out, the fact that these coated, iron oxide nanoparticles are already being used safely,

as contrast agents to increase the precision of detecting abnormalities by MRI, makes their use much more attractive to explore their efficacy to kill cancer. He feels it is important to focus on developing the basic technology, heating the nanoparticles with alternating magnetic field devices, as a more direct route to clinical trials, as well as a way to determine the likelihood of success for nanoparticle technologies in cancer care. Presently, Dr. Ivkov and his research team are refining the choice of nanoparticles and working out details of heating the particles in both cells and animals bearing human tumors. This work directly supports the goal of the first human clinical trial, in which the heating component of nanotechnology will be integrated with the radiation treatment. In theory, an MRI scan would reveal the location of iron oxide-impregnated cancer cells presently undetectable by routine scanning methods. These nanoparticles would then be heated right before radiation or chemotherapy is delivered, thereby increasing the effectiveness of each. In keeping with the Johns Hopkins philosophy of a multidisciplinary team effort, Dr. Ivkov works on this project with different collaborators who possess complementary expertise and knowledge. Dr. Ivkov particularly notes his collaboration with Shawn Lupold, Ph.D., assistant professor in the Department of Urology. Dr. Lupold is an expert in molecular targeting and is primarily responsible for helping Dr. Ivkov with designing molecules to direct the nanoparticles to cancer cells. Dr. Ivkov is also pursuing work on the blood/brain barrier with fellow Radiation Oncology and Molecular Radiation Sciences assistant professor Eric C. Ford, Ph.D., whom we introduced in our inaugural issue of On Target. Until two years ago, Dr. Ivkov’s nanotechnology did not exist. Now, the data Dr. Ivkov and his colleagues are collecting in the laboratory is moving the research toward the clinic; from the theoretical to the reality of treatment in the continuum of patient care that is the standard for the Department of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins. ■

ON TARGET • winter 2009

Cancer Damage Control pose of the laboratory. Dr. Laiho knows she is helping to create the next generation of topnotch scientists. She recently recruited assistant professors Sonia Franco, M.D., Ph.D., and Mihoko Kai, Ph.D., to work specifically on various aspects of DNA-damage response; how cells sense and repair this damage. The sensing, detecting, and repairing of DNA lesions are of vital importance in maintaining genomic integrity. In advanced cancer, many pathways that govern proper DNA-damage control are lost. Conditions prevail which augment the accrual of genetic errors, which leads to the proliferation of cancerous cells. When tumors are targeted by radiation, powerful signals are leashed in the cell, which together with the physical damage, lead to the death of the cancer cell. Because of the many genetic lesions already present in the cancer cell, and the inability of tumor cells to repair effectively the excess of the damage, the damage overload proves critical. Several modes of cancer therapies, including many cytotoxic drugs, exploit this vulnerability of tumor cells. Dr. Laiho is particularly interested in the function and regulation of the key DNA-damage response protein, the p53 tumor suppressor. The p53 protein is one of the crucial chains being mutated in most human cancers. Although medical scientists around the world are investigating p53, Dr. Laiho focuses specifically on the mechanisms mediating the activation of p53 in response to cell stress, and, on attempts to revoke its activity. The activation of this protein may be involved in the sensitivity of cancer to radiation. P53 and DNADr. Laiho examines how nordamage mal tissues respond to radiation. She has observed altered p53 and checkpoint DNA-damage checkpoint reresponses in the sponses in the prostate gland and posits that “our observations… prostate gland indicate that the relaxed damindicate relaxed age control could predispose the prostate to the highly frequent damage control tumorigenic processes observed could predispose clinically.” Dr. Laiho’s goals are: to the prostate to acquire groundbreaking inforthe tUmorigenic mation on the regulation of processes observed cellular DNA damage and tumorigenesis pathways; to provide clinically. novel, lead compounds that activate p53 for preclinical trials; and to identify novel targets for therapy. Dr. Laiho aims to narrow, if not close, the gap between research and its clinical application, between present knowledge and research goals and the future aims of science, medicine, and the work of Johns Hopkins. Dr. Laiho’s work is part of the multidisciplinary continuum at Johns Hopkins, as basic research flows from the laboratory to the clinic to benefit all patients who come here seeking treatment for cancer. ■

Dr. Marikki K. Laiho leads a team investigating the p53 protein and cancer.

fter an extensive, two-year search for a world-class research scientist and program leader, in August, 2007, Theodore L. DeWeese, M.D., department chairman of the Department of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins, hired Marikki K. Laiho, M.D., Ph.D., as the new director of the Division of Molecular Radiation Sciences. Dr. Laiho was the director of the Molecular Cancer Biology Program at the University of Helsinki. With a background in cancer biology, Dr. Laiho brings her expertise in DNA-damage signaling to her laboratories at Johns Hopkins and in Helsinki. At Johns Hopkins, Dr. Laiho leads a research division that focuses on the basic, mechanistic aspects of cellular responses to genetic lesions. When many lesions go undetected, five to ten critical sites in a cell’s DNA may unhinge the normal cell. She seeks to understand the mechanisms involved in the conversion of normal cells to cancer cells. The question of how cancers originate is extremely relevant to the practice of radiation oncology and the field of radiobiology, the science of how damage lesions are generated and how repaired. Dr. Laiho manages her laboratory by allowing team members, including students, to take relatively independent charge of their projects. The scientists formulate different research questions and focus their work accordingly, while being cognizant of the overall objective of the laboratory and their contribution to it. The researchers frequently meet with Dr. Laiho to discuss progress. Dr. Laiho trusts those under her supervision to use their technical skills to make rational decisions, but, she stresses her role in the training pur3

ON TARGET • winter 2009

The Scale of Cancer Treatment

eet John Wai-Chiu Wong, Ph.D., director of the Divi-

sion of Medical Physics and professor of radiation oncology in the Department of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins. Dr. Wong manages the physics and the dosimetry services of the department to ensure the delivery of state-of-the-art methods of radiation treatment to each patient. Theodore L. DeWeese, M.D., department chairman, recruited Dr. Wong for Johns Hopkins because of his work in applied medical physics. With colleagues at the William Beaumont Hospital in Michigan, Dr. Wong developed the technology that gives radiation oncologists the ability to create CT images at the same time the patient receives radiation. This novel radiotherapy device, the patented Elekta Synergy® machine was first produced in 2004 and is now used worldwide. With the invention of Synergy®, Dr. Wong played a leading role in ushering in the era of image-guided radiation therapy (IGRT). What makes the Synergy® revolutionary is the utilization of a cone-shaped beam of X-rays to create a 3-D view of the target area. The system captures the images in a single, one-minute revolution. Soft tissue tumors can be identified without the need for implanting markers, eliminating the need for needle insertion. Because the imaging component of the Synergy® operates in real time and is integrated with the radiation component, medical specialists can position the beam more accurately on the target area, making adjustments as they proceed, creating tighter margins, and preserving more healthy tissue, with a minimal time lag between the imaging of the cancer and the delivery of the radiation to destroy it.

Dr. Wong uses his Elekta Synergy® and Active Breathing Coordinator™ to fight cancer.

Dr. Wong also invented the Active Breathing Coordinator™ (ABC™), a device which assists the patient in holding a volume of breath, at a simple and repeatable threshold, during preliminary imaging examinations and during treatment. By facilitating the patient’s breath hold, images can be taken and radiation delivered at the precise moment of this pause in breathing. More accurate images and less healthy tissue irradiated are just two of the many benefits of the ABC™ for J o h n s H o p k i ns now has t he tool patients. Like the Synergy® t o t r e a t c a n cer in m ice th a t machine, the ABC™ g r e atl y i m p roves t he t ransla t ion is used worldwide by o f n o v e l tr eat ment met hods from radiation oncologists. In the spirit of coopt he l ab o r a t or y to th e cl in ic. erative teamwork at Johns Hopkins, Dr.

Wong’s colleague, Richard C. Zellars, M.D., is currently engaged in a study, described in this issue, to prove that the ABC™ prevents heart damage during left breast radiation treatment. Dr. Wong came here in 2004, where he proceeded to make a scaled-down version of Synergy® that could be used to treat mice. Dr. Wong created the small animal radiation research platform (SARRP) because he realized that, in order to increase the efficacy and usefulness of animal studies, the crucial bridge between theoretical research and clinical trials involving people, better technology needed to be developed for animal work. While the technology for humans was becoming more and more sophisticated, in large part thanks to his own contributions to the field, machines used for animal work had not changed in more than 25 years. (continued on page 6)

ON TARGET • winter 2009

Zooming in on Breast Cancer

eet Richard C. Zellars, M.D., assistant professor of oncology and radiation oncology in the Department of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins. We are proud to report that Dr. Zellars is a graduate of the Johns Hopkins University School of Medicine. Board Certified by the American Board of Radiology in Radiation Oncology, Dr. Zellars has just completed a successful 25-patient Johns Hopkins clinical trial combining chemotherapy with partial breast irradiation (PBI) to treat breast cancer. Before Dr. Zellars’ successful trial, the most common sequencing method of radiation and chemotherapy was chemotherapy first, followed by radiation. This sequential treatment lowered rates of toxicity but prolonged the overall treatment course. Dr. Zellars decided to combine PBI with, arguably, the most common modern chemotherapy, dose-dense doxorubicin and cyclophosphamide. Dr. Zellars’ team was the first to show that this combination of radiation and chemotherapy can occur with no toxic side effects. The most immediate benefit to women is that the overall breast cancer treatment time is reduced from what was commonly a five-to-six month treatment course to one that lasts less than two months, allowing women to get back to their fully active lives much sooner. Dr. Zellars notes: “The research mission of our patient centered breast program is not only to facilitate breast radiation therapy, but, also, to increase its efficacy and, most importantly, safety.” Besides making combination therapy safe and effective for breast cancer, Dr. Zellars is also investigating improving treatment by more accurately locating the lumpectomy cavity by applying PET scanning technology. With PBI, it is tremendously important to target the correct area to spare as much healthy tissue as possible. Dr. Zellars and his team of medical experts at Johns Hopkins improved on the technique of tumor localization by using a PET scan, which is exceptionally good at picking up inflammation, to detect cancer in the body. The PET scan produces a 3-D image of the lump cavity after a lumpectomy has been performed. If the entire wall is inflamed, it can be used as a marker at which to aim radiaT h i s c o m b i n at ion tion. In his role as educator as o f r a d i ati o n and well as clinician, Dr. Zellars is c hem o t h e r a py working with Johns Hopkins a l l o w s w o men t o engineering graduate students to develop a new ultrasound g et b a c k t o t heir technique, ultrasound elasticity imaging (USEI). f u ll y a c t i ve l iv es Normal breast tissue, scar m u c h s oon e r . tissue, and the lump cavity all have different types of elastic-

Dr. Zellars explores novel ways to combat breast cancer.

ity. When women enrolled in the trial get a CT scan, they will also receive the new ultrasound to see if the ultrasound image can identify the cavity as well as, if not better than, the CT scan. This is important because women receiving daily radiation treatments can be exposed to too much radiation when the targeted area has to be localized with frequent X-rays. An ultrasound image, however, may be able to provide a more precise target location than X-rays. An additional benefit is that this ultrasound technique can be used daily without any risk to the patient. As with Dr. Zellars’ PET scan improvements, USEI is leading to less healthy tissue being irradiated; a safer and more precise application of radiation. Members of the Department of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins build on each other’s work to take cancer care to the next level. Dr. Zellars is presently conducting a cardiac tissue toxicity trial using a medical device created by his colleague, John Wai-Chiu Wong, M.D., who is also profiled in this issue. Four years ago, scientists at Duke University demonstrated that radiation delivered to the left breast decreased blood flow to the heart and (continued on page 6)

ON TARGET • winter 2009

Zooming in on Breast Cancer (continued from page 5)

his research team will, for the first time, examine cytokines and their relationship to breast cancer and patient response to radiation therapy. Cytokines are proteins and peptides that help run cells. Certain cytokines are signs of the development of breast cancer, as others indicate radiation toxicity. Dr. Zellars and his team will be taking blood to check cytokine levels. Changes caused by radiation will be predictive of toxicity and how patients will fare from treatment. All of Dr. Zellars’ clinical studies of breast cancer and related topics fit into the mission of the Department of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins, which is to discover and implement the best treatment for cancer patients. ■

caused heart problems 15 or more years after breast cancer treatment. Meanwhile, Dr. Wong developed the Active Breathing Coordinator™ (ABC™), a device that allows the patient to hold her breath at a certain volume during treatment, allowing the chest wall to expand and move the breast away from the heart, and the heart away from the radiation. Dr. Zellars has set out to prove that the ABC™ device prevents heart damage during left breast radiation treatment. One half of the female patients enrolled in the study are using the ABC™. All of the women had heart scans before receiving radiation and will have another heart scan six months after treatment ends. Changes in blood flow will be traced. This exciting trial should be finished by the end of the year. We are pleased to announce Dr. Zellars’ latest Johns Hopkins clinical trial, which has just been funded and will begin shortly. Dr. Zellars and

The Scale of Cancer Treatment (continued from page 4)

SARRP was built by a Johns Hopkins multidisciplinary team, including members of the robotics engineering group of the Homewood campus computer science department. They built the machine and moved it to the Department of Radiation Oncology and Molecular Radiation Sciences in 2007, where seven different projects are currently under way. Each member of the department has the opportunity to operate the machine and learn how the system works. Like Synergy®, the SARRP has cone-shaped beam X-ray capabilities, again allowing for 3-D imaging of the target area, and a flatpanel detector. Unlike Synergy®, robotics are

used to rotate the stationary animal between the X-ray source and the detector. The X-ray source is mounted on a gantry. The sophisticated image-guidance system produces high resolution images. The SARRP is a powerful tool for the Johns Hopkins cancer research scientists, enabling them to study focal radiation of the tumor and organ system of the laboratory animal. Computer-controlled targeting allows the researchers to study mice organs, such as the lungs, or, a small region of the brain, which harbors stem cells. Experiments are designed to evaluate the effectiveness of novel treatments and

K I M M E L C A N C ER C ENTER

Make a Gift There are a number of ways to support the Department of Radiation Oncology and Molecular Radiation Sciences. To find out about our priority programs and how you can help to fund one of them, or, to designate a gift to a specific program, a research project or a fund-raising event, contact: Marie Jo Corry Fund for Johns Hopkins Medicine 100 North Charles Street, Suite 234 Baltimore, Maryland 21201 410-516-4849

treatment-related toxicity in the small animal model. The Radiation Oncology and Molecular Radiation Sciences team now has the tool to treat cancer in mice that greatly improves the translation of novel treatment methods from the laboratory to the clinic. About his work in the Department of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins, Dr. Wong asserts: “We can learn so much more about each individual patient, such that the treatment can be transformed from a traditional treatment strategy that fits the larger patient appellation to one that is specifically customized for each patient.” ■

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Contact

Johns Hopkins Radiation Oncology at Greenspring Station 10753 Falls Road Pavilion 2, Suite 145 Lutherville, MD 21093 Radiation Oncology Services Main Number: 410-847-3800 Referrals: 410-502-8000 Fax: 410-947-3803

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ontarget KIMMEL CANCER CENTER

A publication by the Department of Radiation Oncology and Molecular Radiation Sciences of The Johns Hopkins School of Medicine Writer Catherine Keim Copy Editor John Bartgis Designer Vladimir Rajevac Photographer Keith Weller © 2009 The Johns Hopkins University and The Johns Hopkins Health System Corporation.

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