Mechanisms of uveal melanoma dormancy and targeted therapy tolerance

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The clinical landscape of metastatic melanoma has advanced rapidly since 2009 with the breakthroughs of targeted therapies and immunotherapy. These therapeutic agents are now moving into the adjuvant setting. A current unmet need is to understand the biology of melanoma that fail to respond to either targeted or immunotherapy in order to devise new treatment strategies. A paradigm for these non- responsive subsets is uveal/ocular melanoma. A further complication is that nearly 50% of uveal melanoma patients will ultimately develop advanced disease involving liver metastasis without recurrence at the primary site; however, there is often a lag period ranging from years to decades between primary tumor treatment and development of liver macro-metastasis. This observation highlights the clinical importance of early tumor cell dissemination (DTC) and dormancy at distant sites. We are studying the cellular mechanisms of tumor dormancy and tolerance to targeted inhibitors in uveal melanoma. We aim to identify mechanisms controlling dormancy in uveal melanoma disseminated tumor cells. Mechanistic insights will lead to novel targeting approaches; thus, we aim to provide pre- clinical data for new treatment combinations for uveal melanoma patients. Aberrant cell cycle regulation is a hallmark feature of cancer. In uveal melanoma, cell cycle progression is promoted through mutations in the guanine-nucleotide binding proteins, GNAQ and GNA11. Selective CDK4/6 inhibitors are FDA- approved in ER-positive/HER2-negative breast cancer but their use in uveal melanoma will require optimization of drug combinations and schedules. We aim to understand how to utilize CDK4/6 inhibitors in uveal melanoma and combine them with agents that target dormant cells and/or drug tolerant persisters. We aim to define the molecular signatures of these therapy-induced drug tolerant persisterp cells in metastatic uveal melanoma. In this multi-PI R01, synergy is provided by our established published and ongoing collaborations on altered signaling pathways, cellular dormancy, metastasis biology and response to targeted therapies. Our research expertise in dormancy and melanoma biology complement each other and link to clinical strengths at our institutions. Our studies will determine how dormancy and oncogenic signaling pathways dictate survival and quiescence of uveal melanoma DTCs and how to target them to prevent metastatic re-growth. We anticipate that our mechanistic insights into uveal melanoma DTCs and metastasis biology will form the basis for new treatment options that in the near future could result in more potent and durable therapy responses.