Inhibition of BET Bromodomain Proteins in Uveal Melanoma

Uveal melanoma (UM) is an aggressive malignancy with no effective therapy available in the metastatic setting. Recently, our team identified a novel strategy for targeting UM via inhibition of bromodomain containing 4 (BRD4), a conserved member of the bromodomain and extraterminal (BET) family of transcriptional regulators. In this proposal, we will combine the efforts of experienced laboratory and clinical investigators from Columbia University Medical Center, New York University, and Thomas Jefferson Hospital Cancer Center, three centers with expertise in the development of novel treatments for UM, with the investigational drug pipeline of Plexxikon to explore the effects of BRD4 inhibition in this rare disease. We will utilize cell line, xenograft, and patient explant tumor models and will conduct a clinical trial to analyze the anti-tumor effects of BRD4 inhibition, analyze the molecular and epigenetic profile changes in UM with BRD4 inhibition, and assess mechanisms of primary and secondary resistance to treatment. Using a large drug library and high-throughput screening program, we will explore the synergistic effects of BRD4 inhibitors with other small molecules in cell culture and mouse models to improve efficacy and overcome potential drug resistance. This proposal will allow us to expand our understanding of the mechanisms of BRD4 targeting and provide a novel therapeutic option for patients with UM.