As a pediatric hematologist/oncologist at Children’s Hospital in Boston, Leonard Zon says, “I certainly never expected I would end up working with fish.” Dr. Zon studies a unique organism: the zebrafish. This one and a half inch fish happens to have a gene set that is very similar to the human gene set. Zon is a pioneer in the zebrafish field and chose to model human diseases using this fish because, “the zebrafish embryo is completely clear, providing a ‘real time’ view of all organs and systems as they develop.” With 3,000 tanks in his lab, he has one of the largest aquaria in the world.
Dr. Zon’s recent work brings new hope to melanoma patients. His laboratory has developed a zebrafish model of human melanoma. His team used this unique model to screen 2,000 chemicals that target melanoma cells and interfere with their growth. The screen found one drug, called leflunomide (an approved arthritis drug), which blocked the melanoma growth by interfering with the cancer cell and causing it to lose many of the characteristics of a melanoma. This is an example of how an approved drug for one disease can be successful against other diseases as well.
Zon’s research is currently being funded by a MRA Team Science Award. His team, including Richard White (MSKCC) and Keith Flaherty (Massachusetts General Hospital), combined leflunomide with the BRAF inhibitor and discovered that combining the two may be better than the BRAF inhibitor alone. With MRA’s support, Zon’s laboratory was able to complete preclinical testing and translate these studies into a clinical trial. Their work is currently part of a Phase 2 trial of the combination therapy to target molecular and cellular fate pathways. This groundbreaking research not only brings new hope to melanoma patients but may also benefit those suffering from other cancers.
Dr. Zon received a B.S. in chemistry and natural sciences from Muhlenberg College and his M.D. degree from Jefferson Medical College. Zon is currently the Gorusbeck Professor of Pediatric Medicine at Children’s Hospital Boston of Harvard Medical School, an Investigator with the Howard Hughes Medical Institute, and Director of the Stem Cell Program at Children's Hospital Boston. In addition to these positions, Dr. Zon is President of the International Society for Stem Cell Research, President of the American Society for Clinical Investigation, Head of the external investigators of the Zebrafish Genome Institution and Chairman of the Harvard Stem Cell Institutes Executive Committee.
Outside of research and medicine, Dr. Zon’s passion is music. He has played first trumpet in the Longwood Symphony Orchestra for the past 28 years. Additionally, he enjoys spending time with his family, especially attending his children’s soccer matches with his wife.
Medical research is fraught with challenges, and melanoma poses an especially difficult set of questions. Researchers who work to better understand the disease and develop new treatments must be highly motivated. Some pursue cancer research because they have been touched by the disease themselves, and some are motivated by the intellectual challenge of the cancer puzzle. Exemplifying the latter, Dr. Timothy Bullock chose to pursue melanoma research because "it is a fascinating disease from the perspective of how the immune system interacts with it." Bullock is an Associate Professor in the Pathology Department at the University of Virginia (UVA) where his lab is part of the Human Immune Therapy Center.
Bullock grew up in the United Kingdom, and his interest in science was stimulated by his mother's work in the pharmaceutical industry. He fondly remembers summer holidays splitting time between working in the immunohistochemistry labs and harvesting brambles for the lab's pet stick insects. He studied Microbiology at Leeds University, went on to receive his Ph.D. from Thomas Jefferson University in Philadelphia, and finally completing his post doctorate work at UVA.
Trained as an immunologist, Bullock is specifically interested in working out aspects of the relationship between melanoma and the immune system. "Melanoma is a challenge. The immune system appears to recognize melanoma since immune cells are present in it, yet the disease progresses," he says. Bullock is focused on figuring out why that happens with the goal of developing new treatment approaches to boost the immune system against cancer. Specifically, he focuses on how T cells, which are normally responsible for killing melanoma cells, are seemingly inactivated in patient tumors. With that knowledge, he hopes his lab can work on a vaccination approach to reactivate T cells to eradicate the disease in patients.
As an early career scientist in cancer research, Bullock received an MRA Young Investigator Award in 2008 as part of the first "class" of MRA Young Investigators. This support helped his lab optimize a therapeutic melanoma vaccination strategy designed to boost the T cell response to specific targets expressed by melanoma cells. In 2011, Bullock was awarded one of the first MRA Academic-Industry Partnership Awards, a grant that is designed to facilitate interactions between the academic and industrial research sectors. This project, which is being jointly supported by MRA and Celldex Therapeutics, focuses on determining whether an antibody that stimulates CD27 on immune cells will activate them against melanoma. These research studies are being conducted in the context of a phase I clinical trial.
Bullock says that MRA funding has been critical to the success of his career; not only through research funding but also through the many other opportunities that MRA creates for its funded investigators to enhance collaboration. "The MRA has provided my laboratory the opportunity to grow in scope, achievement, and outreach. MRA is a motivational organization that brings together the research community. At the end of each interaction we find ourselves highly invigorated to take on this very challenging disease," he says.
Levi Garraway admits melanoma was not on his radar screen when he started in research. He began his research career studying prostate cancer when his father was diagnosed and ultimately died of the disease about a decade ago. However, the sometimes serendipitous nature of research can catalyze new opportunities. “I became interested in melanoma because one of the first major observations that we had in the lab ended up being highly relevant to melanoma. At that time there was an urgent need to do the kinds of research I was doing in melanoma, and it was also clearly an unmet medical need,” he says. Garraway ultimately created a large research program in melanoma, which has now become his lab’s focus. Garraway leads several large cancer genome efforts, and this research has accelerated the identification and validation of several genes and cellular pathways involved in melanoma and other cancers. These results have the potential to lead to new targets for drug development.
Garraway is an Associate Professor of Medicine in the Department of Medical Oncology at Harvard Medical School/Dana-Farber Cancer Institute and Senior Associate Member of the Broad Institute of Harvard and MIT. He received his M.D. and Ph.D. degrees from Harvard Medical School in 1999. Thereafter, he completed his internship and residency in Internal Medicine at the Massachusetts General Hospital, where he also served as Medical Chief Resident in 2003. He received fellowship training in medical oncology at the Dana-Farber Cancer Institute. A rising star in cancer research, Garraway has received several honors and awards, including a first prestigious New Innovator Award from the National Institutes of Health, which supports promising early career scientists with exceptionally innovative research ideas.
Garraway is a leading investigator in several MRA funded Team Science Awards. One of these, a project with Michael Weber, Ph.D. and Dan Gioeli, Ph.D. at the University of Virginia Cancer Center, focuses on gene silencing techniques to search for the most effective combinations of drugs to kill melanoma cells. Another, with David Hoon, Ph.D. at the John Wayne Cancer Institute, and David Fisher, M.D., Ph.D. at Massachusetts General Hospital, is characterizing subtypes of melanoma and using this knowledge to design new therapies. He says MRA’s team science mechanism is beneficial for two reasons: “It creates an incentive for people to work together who might otherwise never have the opportunity, and it supports the kind of research that, if it comes to fruition, could be highly impactful in the field.”
Optimistic about the future of melanoma research, Garraway says, “There is a certain subset of melanoma where we can start thinking about the right therapeutic combination to give us a durable response and maybe even a cure.” This subset is the approximately half of patients whose melanoma expresses a mutant form of the BRAF gene. Last year, a new drug, called vemurafenib (Zelboraf), was approved for these patients. He says to even be able to talk about a cure of melanoma is a huge advance in the field. Garraway believes the other area that requires the most attention going forward is the other half of melanoma cases, for which there are still no effective options for patients. He attributes recent progress in the field to be the result of organizations like MRA. “MRA provides the ability to have rapid catalytic funding in areas that are likely to impact the clinic. This is something one can do in melanoma that wasn’t doable before. MRA has brought the scientific community together in a special way,” he says.
Padmanee “Pam” Sharma was hooked on science after her first biology class in high school. This interest strengthened as an undergraduate at Boston University when she took her first immunology course and was fascinated by the concept of how the immune system can adapt to recognize and fight off a pathogen or tumor cell that comes its way. “I chose to pursue a career in research and medicine because it gives me a chance to help patients, sometimes simply by being there to explain things during the course of a difficult situation, and to develop research that can have an impact on the future of patient care,” she says.
Sharma completed her M.D and Ph.D at Pennsylvania State University and a medical oncology fellowship at Memorial Sloan-Kettering Cancer Center. During that time, she had the opportunity to apply her understanding of immunology to the clinical setting. Sharma is currently a physician-scientist in the Departments of Genitourinary Medical Oncology and Immunology at The University of Texas M. D. Anderson Cancer Center in Houston, Texas.
Her lab focuses on the development of immunotherapy strategies to treat cancer. One of these strategies involves studies of ipilimumab (anti-CTLA-4), which was approved by the FDA last year to treat metastatic melanoma. Sharma received a MRA Young Investigator Award in 2008 to support her work to understand how to improve ipilimumab by better understanding how different components of the immune system react to the agent and to apply this knowledge so that more melanoma patients respond favorably to the treatment. “I’ve been lucky enough to meet some of the patients who have had incredible responses and are now disease free and living much longer lives. It helps us in the field to realize the impact our research can have” she says. A rising star in cancer research, Sharma has also received prestigious awards from the Prostate Cancer Foundation and the Cancer Research Institute.
As a physician treating cancer patients and as a researcher, Sharma has a unique and powerful combination of talents that are critical to accelerating clinical research. Much of her research is done by leveraging data from clinical trials to obtain clues to the biological basis for the cancer’s behavior. Then, her team takes that information from the patients and develops mouse models to study different ideas and test new treatment approaches in pre-clinical studies. If successful, new treatments can be implemented in new clinical trials. She describes this research process as, “going from the bedside back to the bench and then back to the bedside.”
Echoing the focus of the MRA, Sharma believes significant innovations in cancer research requires a team effort of different investigators, institutions, and sectors working together, which comes from a passion for making an impact on patients. Such collaboration is necessary for the development of combination therapies, which is seen as the future of cancer medicine. “We need companies and academic centers to bring together all of the different reagents, because it’s not going to be a single agent that is going to allow us to beat this disease. It’s going to be multiple agents together, and we have to be able to combine them in order to cure melanoma.”
As a student, Edwin Bremer quickly discovered his interest in the physiology of the human body, and the immune system in particular. Bremer chose to investigate the intricate interplay between (pre)cancerous cells and the immune system and to try to find ways of exploiting and restoring anti-cancer immunity. Having family members affected by cancer has been a driving force for his work.
Bremer describes himself as being new to melanoma. Since there are few treatment options for patients diagnosed with late stage melanoma and life expectancy is very limited, Bremer felt new approaches that block the spread of metastasizing (spreading) cells were urgently needed. Bremer and his research team realized that the concepts they established in other tumor types would be particularly suitable for this type of cancer. So they shifted their focus to the treatment of melanoma.
Bremer and his team aim to develop novel approaches based on two proteins normally involved in the fight against cancer in the human body, TRAIL and Galectin-9. TRAIL can induce cell death in melanoma cells, but not in normal cells, whereas Galectin-9 specifically blocks the ability of melanoma cells to metastasize.
Bremer’s team fused TRAIL and Galectin-9 to a so-called antibody fragment that targets melanoma cells. Once the melanoma cell has been recognized, the second part of the protein kills the tumor cell. Bremer likes to compare this new strategy to the “smart bomb.” He says, “The idea with the smart bomb is that you deliver your explosive only where it needs to be. We try to deliver something that can kill off only melanoma cells.” Bremer envisions that this approach will eventually be applied after surgery to prevent the establishment and growth of metastatic lesions and potentially in combination with chemotherapy.
Bremer’s type of collaborative, translational research ideally represents MRA’s focus on bringing new treatments to patients as quickly as possible. “With my lab based in the department of surgery, I keep close contact with the surgeons to ensure we work towards the goal of integrating our new approach into clinical practice,” he says.
His innovative work is being supported by the SkinCeuticals-MRA Young Investigator Award. As a young scientist, the challenges to establishing a research career are significant. In addition to tackling a problem as complex as cancer, funding and support are critical. Bremer considers MRA’s funding to have greatly facilitated his research: “MRA has helped accelerate my research by providing me with the critical resources needed to increase the pace of my research and to develop better treatments for patients.”
Bremer received his doctorate in medical sciences from the University of Groningen in the Netherlands. He is currently in the laboratory for Translational Surgical Oncology at the University Medical Center Groningen. Outside the lab, much of Bremer’s time is dedicated to his family, spending as much time as possible with his two young boys and “watching them explore the world themselves.” He also enjoys outdoor sports and has recently discovered a passion for the Dutch past time of speed-skating.
Last May, during Melanoma Awareness Month, Bremer answered questions about preventing and treating the deadly skin cancer on Facebook.
Hensin Tsao learned to fear, and respect, cancer at an early age when he witnessed his grandmother pass away from ovarian cancer. Despite his inability to understand the science behind his grandmother's death, young Tsao saw the devastation that cancer caused his loved ones.
Years later Tsao pursued a medical degree, specializing in dermatology, along with a doctorate in biophysics and biochemistry. He currently supervises a laboratory at Massachusetts General Hospital focused on the genetics of melanoma. Tsao's decision to focus his career on melanoma rather than another type of cancer is a result of his belief that "melanoma represented the greatest challenge." He explains that studying melanoma skin cancer "really is medicine, mystery, and mission all wrapped up in one. Every time we think we understand the disease, something unexpected emerges, which drives us back to the laboratory for more."
Cancer is caused by mutations in a cell's genetic makeup - sometimes through the exposure to environmental insults (UV radiation), toxic chemicals, and other factors - which cause the cells to change, grow, and invade other tissues. Tsao and his team are working to identify these crucial mutations and how they impact the behavior of melanoma cells in order to suggest how targets can be leveraged toward finding a cure. Tsao calls this research approach "target practice."
Tsao's research has been funded by an MRA Team Science Award. Thanks to the award, Tsao is collaborating with David Solit, M.D., Memorial Sloan-Kettering Cancer Center, and seven other research leaders from six different institutions to identify causes of resistance to a class of drugs called BRAF inhibitors. The first BRAF inhibitor was approved by the FDA in August 2011. Despite a high response rate to the drug, a majority of patients relapse due to drug resistance. The collaborative effort, a hallmark of the MRA research program, allows Tsao and the team to reach more patients and acquire more information. "We can create a virtual cloud of phenotypes and genotypes, which we work collaboratively from."
The Tsao and Solit team was created in part by MRA seeing the transformative potential of a combined effort. Rather than two groups led by Tsao and Solit separately, MRA proposed a merger to create a collaboration of six world-class centers conducting trials of BRAF inhibitors. Tsao believes that "the Melanoma Research Alliance recognizes the fact that the collaboration of experts in multiple fields is a faster, more effective method of cancer research. A research team allows you to focus on your own scientific game while partnering with other experts to accelerate progress." In addition to producing results more quickly, this collaboration is important when dealing with complex science. "The Team Science Award is a perfect example of how win-win scenarios can be created and orchestrated."