Preclinical investigation of a small molecule inhibitor of p300/CBP reveals efficacy in patient-derived prostate tumor explants.

Abstract

e16534 Background: Growth and survival of prostate cancer cells are initially dependent upon androgens, and androgen deprivation therapy (ADT) is used to control tumor growth. Unfortunately, resistance to ADT inevitably occurs, and patients relapse with lethal castrate-resistant prostate cancer (CRPC). Increased expression of the androgen receptor (AR) and constitutively active AR variants are hallmarks of CRPC, and treatments targeting aberrant AR signaling are urgently required. CCS1477 is an inhibitor of p300/CBP currently in a Phase I/IIa study for CRPC. CCS1477 enhances degradation of numerous cellular proteins including the AR and AR variants in prostate cancer cells. Our preclinical studies with this compound demonstrated potent single-agent efficacy of CCS1477 using in vitro and in vivo models of prostate cancer and, when used in combination, CCS1477 enhances the efficacy of enzalutamide, a clinical AR antagonist. Understanding the response of clinical tumors to CCS1477, and their potential adaptive evolution, is essential to personalize treatment and predict potential resistance mechanisms. Methods: To assess CCS1477 in human disease, we used a unique model in which clinical prostate tumors from radical prostatectomy are cultured as explants with maintenance of tissue integrity, cell proliferation and androgen signaling. Tumors from 13 patients were cultured in the absence or presence of CCS1477 (10µM) or enzalutamide (10µM) for 48 or 72 hours; micromolar doses were selected to account for altered small molecule uptake and penetration into tissues compared to cell lines, as previously reported. Proliferation, apoptosis and androgen signaling were all analyzed post-culture. Results: Whereas the tumor explants exhibited highly heterogenous proliferative responses to enzalutamide, tumors from all patients exhibited a marked antiproliferative response to CCS1477 (mean reduction in Ki67 immunoreactivity of > 90% compared to vehicle control; p < 0.0005). Culture with CCS1477 was associated with repression of androgen signaling in the prostate tissues, measured by expression and secretion of the clinical biomarker prostate specific antigen (PSA). Conclusions: The consistent and pronounced efficacy of CCS1477 in this patient-derived model would support further investigation of this class of epigenetic agents in the castrate-sensitive prostate cancer setting.