Defining and targeting the epigenetic landscape of uveal melanoma
PRINCIPAL INVESTIGATORS:
Keiran Smalley, PhD (H. Lee Moffitt Cancer Center)
Jonathan Licht, MD (University of Florida Health Cancer Center)
William Harbour, MD (University of Miami Sylvester Cancer Center)
Uveal melanoma is a highly aggressive form of cancer that exhibits a propensity to metastasize to the liver. At this time there are no effective treatments for metastatic uveal melanoma and new therapeutic strategies are urgently needed. The majority of uveal melanomas are driven through activating mutations in the G-proteins GNA11 and GNAQ that appear to confer sensitivity to inhibitors of MEK, PI3K and PKC, (at least in preclinical models). Despite this, MEK inhibitor monotherapy has proven ineffective against disseminated uveal melanoma in the clinic, suggesting that a combination strategy may be required. Inactivating mutations in the tumor suppressor BAP1 are associated with loss of melanocytic differentiation in uveal melanoma and metastasis. Recent work from our group has shown that epigenetic modifiers, such as HDAC inhibitors, induce differentiation and cell cycle arrest in uveal melanoma cell lines and can inhibit the growth of uveal melanoma xenografts in vivo. Initial studies in cutaneous melanoma have also suggested a role for HDAC8 in the adaptive signaling observed following BRAF and MEK inhibition, as well as metastatic dissemination. A link between these studies and uveal melanoma is suggested by our observation that HDAC8 is highly expressed in uveal melanoma cell lines and patient samples, and that its expression is differentially increased in uveal melanoma patient samples that are mutant for BAP1. The goal of this proposal is to determine the role of HDAC8 in regulating the epigenetic and signaling landscape of high-risk uveal melanoma which is characterized by loss of function of the ubiquitin ligase BAP1 and frequently gain of function of the GNA11 or GNAQ proteins. Specifically, we will determine the mechanism by which HDAC8 maintains the aggressive, de-differentiated phenotype of uveal melanoma and determine how BA1 and GNAQ mutations alter gene expression, epigenetic features of the genome and lead to a high dependence on HDAC8 activity. Further studies will investigate whether inhibition of HDAC8 potentiates the efficacy of MEK inhibitors through limiting adaptation in the pathway.
