Despite recent advances in therapy, melanoma remains the deadliest, most aggressive form of skin cancer as incidence rates continue to climb. Now, a team of melanoma scientists from The Wistar Institute and the University of Pennsylvania received a $12.5 M, five-year program project grant (P01) from the National Institutes of Health to continue trailblazing research on targeted therapies in melanoma.
Team leader Meenhard Herlyn, D.V.M., D.Sc., director of Wistar's Melanoma Research Center and professor in the Institute's Molecular and Cellular Oncogenesis Program, brought together a team of melanoma scientists to study the intractable problem of melanoma drug resistance.
"Inevitably, advanced melanoma becomes resistant to drug therapy, and despite the new BRAF inhibitors that have proven very successful during initial stages of treatment, the disease returns stronger than before," said Herlyn. "We can overcome this drug resistance by utilizing a deeper understanding of melanoma biology to develop more effective therapies or new methods of boosting the effectiveness of existing therapies."
"This grant enables scientists from different backgrounds-tumor biology, structural biology, chemistry, pathology, oncology, and biostatistics-to pool our talents and tackle melanoma from different vantage points," said Herlyn.
The team includes Maureen Murphy, Ph.D., Wistar professor and program leader of the Molecular and Cellular Oncogenesis Program, associate director of Faculty Development, and associate director for Education; Ronen Marmorstein, Ph.D., Wistar program leader of the Gene Expression and Regulation Program; Jessie Villanueva, Ph.D., Wistar assistant professor of the Molecular and Cellular Oncogenesis Program and member of The Wistar Institute Melanoma Research Center; Ashani Weeraratna, Ph.D., Wistar assistant professor in the Tumor Microenvironment and Metastasis Program and member of The Wistar Institute Melanoma Center; Jeffrey Winkler, Ph.D., Merriam Professor of Chemistry at the University of Pennsylvania; and Ravi K. Amaravadi, M.D., associate professor of medicine at the Hospital of the University of Pennsylvania.
According to Herlyn, there are three major goals of this five-year project. First, they seek to better understand the ultimate fate of dying melanoma cells. Cancer therapies are currently designed to trigger apoptosis (an inherent self-destruct mechanism within cells) or necrosis (the death of the cell outright). However, recent data suggests that two additional fates are common after drug therapy: autophagy (where a cell can survive by digesting damaged portions of itself) and quiescence (a sort of stand-by mode that allows a cell to survive by "riding out" an attack). In particular, the researchers will look for new methods to block cells from using autophagy or any form of hibernation to survive drug therapy.
The second goal of the program will be to generate "second-generation" drugs, where melanoma biologists will team with molecular biologists and chemists to develop new molecular compounds to form the basis of new drugs that are more potent and effective treatments than their predecessors.
The third goal is based on the notion that melanomas are complex tumors, driven by multiple genetic anomalies. As such, the team will develop strategies that pair multiple drugs-both current and experimental therapies-to see which combinations are most effective by targeting different mutations.
The project is supported by five cores, including pathology, cell biology, biostatistics, medical chemistry and an administrative core, which secures a strong infrastructure in support of research.
"This team is positioned to answer important multidisciplinary questions regarding the biology of melanoma cells with the ultimate goal of achieving a cure," said Herlyn. "I am excited for this collaborative effort that will lay the groundwork for new therapies and strategies in melanoma research."
Combination therapy shows promising results in treating stage 3 melanoma