Targeting p300/CBP in renal cell carcinoma

Project Summary/Abstract Renal cell carcinoma (RCC) is a lethal disease whose incidence is on the rise. Clear cell RCC (ccRCC) is the most frequent (75%–80%) subtype of RCC with limited therapeutic options for advanced disease. The lack of sensitivity to chemotherapy and radiation therapy prompted early research efforts into novel treatment options. The introduction of modern therapeutic strategies, including tyrosine kinase inhibitors and immune checkpoint inhibitors, have significantly improved the outcomes of patients with ccRCC. However, despite the therapeutic progress, complete and durable responses have been noted in only a few cases. Furthermore, the clinical behavior of ccRCC is unpredictable and there are no reliable molecular biomarkers to predict disease progression and therapeutic response. p300 (EP300) and CBP (CREBBP) are two paralogous lysine acetyltransferases involved in post-translational modifications of histone and non-histone proteins, as well as co- activation of various transcription factors. Increasing evidence linked p300/CBP to progression, drug-resistance and immune evasion in tumors of various origins. We hypothesize that inhibition of p300/CBP could have significant negative impact on ccRCC progression by reducing tumorigenic potential of ccRCC cells. Our preliminary data support our hypothesis demonstrating that pharmacological inhibition of p300/CBP using a first- in-class selective and orally bioavailable p300/CBP inhibitor CCS1477 decreases HIF-2and PD-L1 protein expression, suppresses ccRCC xenograft tumor growth and induces complete tumor regression when given in combination with cabozantinib. To test our hypotheses and to establish the role of p300/CBP as novel therapeutic targets and potential biomarkers in ccRCC, we propose the following Specific Aims: (1) Examine the therapeutic potential of targeting p300/CBP in ccRCC; (2) Establish the association between p300/CBP expression and clinical outcomes in ccRCC patients.