Mechanisms of uveal melanoma dormancy and targeted therapy tolerance

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.

Grant Number: 5R01CA253977-05
NIH Institute/Center: NIH
Principal Investigator: Andrew Aplin