MRF’s 25th Anniversary: The Impact of Research on Improving Patient Outcomes

In honor of Melanoma Awareness Month, we pair a young investigator’s recently funded innovative research with her mentor’s witness of the impact of research on improving patient outcomes.

Young Investigator Team Science Award: Characterizing the Role of the Hippo Pathway during Melanoma Immunotherapy

Supported by the MRF’s Breakthrough Consortium and Bristol Myers Squibb (MRFBC/BMS)

Genevieve Boland, MD, PhD (Investigator): As a surgeon, scientist and translational researcher, my goal is to learn from our patients’ experiences with melanoma and take clinical observations back to the laboratory to understand the biology of melanoma and the mechanisms underlying patient response (or non-response) to our existing therapies. Our goal is to use this information to create the next generation of trials to improve clinical outcomes. This research is dependent upon the generosity of our patients who participate in our studies and allow us to take their tumors and blood to the laboratory to better understand the underlying biology of their disease. Through these endeavors, we have already begun to understand why certain patients respond to targeted therapy and immunotherapy while other patients do not. These data can lead us to find new therapies and tools for personalized medicine.

Keith Flaherty, MD (Mentor): I came to Massachusetts General Hospital (MGH) in the immediate aftermath of witnessing, first-hand, the watershed event of successful BRAF inhibition leading to rapid and reliable clinical benefit in patients. At the same time that I arrived in Boston, the first evidence of resistance began to manifest. Around that problem we nucleated a team of medical and surgical specialists in melanoma, pathologists and laboratory-based investigators to understand what was behind resistance. As described by Dr. Boland, this approach proved to be transformative. The work of our group, in concert with several others, led to a rapid increase in our understanding of this phenomenon. One year after observing the first evidence of resistance, we were treating patients with a two-drug combination aimed at overcoming resistance in a phase I trial. That combination became FDA approved three years after the first BRAF inhibitor was approved as a single agent.

Building off this foundation, Dr. Boland and I are looking at other pathways that may be biologically important. Work supported by a MRFBC/BMS Team Award is focused on a specific signaling pathway, the YAP/Hippo pathway, which has been implicated in resistance to targeted therapy. Our goal is to use patient materials in parallel with laboratory models (in vitro and in vivo models) to understand the role of the YAP/Hippo pathway in causing resistance to immunotherapy. Through a large data set of melanoma patients, we used “multi-omic” analyses to examine both genetic and non-genetic (epigenetic) differences in patients receiving immunotherapy, correlating these differences with response to immunotherapy. Currently, we are mining these rich data sets to identify new therapeutic drug candidates that may improve upon our current therapies. We have already shown that combining immunotherapy with epigenetic modifiers that change the YAP/Hippo pathway can improve responses to therapy in mouse models of melanoma. We are currently using this pre-clinical data to design new clinical trials in melanoma patients.

The support of the MRF has been critical in allowing us to bridge from the clinic to the laboratory to truly understand the biology of response and resistance to treatment. In the near term, these projects have the potential to be tested in clinical trials. We are fortunate to have a team of clinicians and researchers working together to push the needle forward in the care of our melanoma patients. This

“team science” approach is critical to making continued inroads in overcoming treatment resistance and achieving long-lasting benefits for all melanoma patients. To learn more about topics discussed, please follow this link to watch a webinar by Geoffrey Gibney, MD on Biomarkers and Genomic Testing.

Life-saving advances in melanoma research are made possible by the generosity of supporters like YOU. Please consider a tax-deductible donation today:

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