Enhanced Targeting of CBP/p300 in a Subtype of Metastatic Prostate Cancer

Prostate cancer (PC) is the most frequently diagnosed non-skin cancer in American men. Early-stage PC can be effectively treated with surgery and/or radiation therapy. Metastatic PC, initially castration-sensitive (mCSPC) and responsive to androgen deprivation therapies (ADT), remains incurable as a majority of patients progress to castration-resistant PC (mCRPC) after months to years of treatment. New therapeutic approaches are urgently needed to inhibit metastasis and disease progression at an early stage in mCSPC with the goal of prolonging survival and ultimately cure. HOXB13, a prostate-specific homeodomain-containing transcription factor, is essential for normal prostate epithelium development. HOXB13 continues to express at high levels in adult prostate and regulates epithelial gene expression. In preliminary studies, we observed gradual loss of HOXB13 expression from primary PC to mCSPC and to mCRPC associated with DNA hypermethylation. We identified a metastasis-suppressive function of HOXB13 in inhibiting de novo lipogenesis, thereby suppressing PC cell motility. This is mediated by a novel interaction between HOXB13 and histone deacetylase 3 (HDAC3) that removes histone acetylation (e.g. H3K27ac) to inhibit target gene expression. HOXB13 loss-of-function in aggressive PC unleashes HDAC3 at lipogenic gene enhancers, enabling the accumulation of H3K27ac that is catalyzed by histone acetyltransferase CBP/p300. Thus, the central hypothesis of our study is that HOXB13 loss-of-function leads to enhanced lipogenesis, lipid accumulation, cell motility, and tumor metastasis through a dependency on CBP/p300-mediated epigenetic remodeling, which can be targeted by CBP/p300 inhibitors (p300i). To test these hypotheses, in Aim 1 we will carefully examine the expression of HOXB13 in the full spectrum of human PC, in particular metastatic and CRPC samples, and determine its correlation with key target genes, disease progression, and clinical outcomes. Aim 2 will investigate whether molecular and pharmacological inhibition of CBP/p300 abolishes HOXB13 loss-induced de novo lipogenesis and cell motility. Finally, Aim 3 will evaluate whether HOXB13 loss sensitizes prostate cancer to a clinically available CBP/p300 inhibitor CCS1477, in particular in terms of cell motility and tumor metastasis, using preclinical PC models. These results will set the stage for a clinical trial of CCS1477 in a subtype of aggressive PC patients, likely in the early phase of mCSPC, to suppress tumor metastasis and disease progression.