Targeting P300/CBP in renal cell carcinoma

The National Cancer Institute awarded The Institute For Cancer Research a $483,395 Project Grant under the Cancer Treatment Research program (CFDA 93.395) beginning September 1, 2025, and concluding August 31, 2027. This research initiative focuses on investigating P300 and CBP (Cyclic AMP-Response Element Binding Protein) as novel therapeutic targets in renal cell carcinoma (RCC), specifically clear cell RCC (ccRCC). The project will examine the therapeutic potential of P300/CBP inhibition, establish associations between P300/CBP expression and disease progression, and identify molecular biomarkers to predict therapeutic response. The research leverages preliminary data demonstrating that the selective P300/CBP inhibitor CCS1477 decreases HIF-2α and PD-L1 protein expression, suppresses tumor growth in ccRCC xenograft models, and induces complete tumor regression when combined with cabozantinib.

The research deliverables encompass preclinical laboratory studies designed to advance understanding of P300/CBP mechanisms in ccRCC pathogenesis and drug resistance, with the ultimate objective of identifying predictive biomarkers and establishing the scientific rationale for P300/CBP-targeted therapeutic strategies. As a nonprofit research institution and subsidiary of Temple University located in Pennsylvania, The Institute For Cancer Research will conduct this research leveraging its established expertise in cancer biology, preclinical drug development, and biomedical research capabilities.

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.