Enhanced Targeting of CBP/p300 in a Subtype of Metastatic Prostate Cancer
Abstract
Scientific Rationale, Objectives, and Aims: 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 (mHSPC) and responsive to androgen deprivation therapies (ADT), coupled with androgen receptor pathway inhibitors (ARPi) such as enzalutamide, remains incurable, as many of them progress to castration-resistant PC (mCRPC) with a median survival of 4-6 years. New therapeutic approaches are urgently needed to inhibit metastasis and disease progression at an early stage in mHSPC to provide ultimate cure. Diet and obesity are major risk factors of PC. Accumulating evidence suggest that aggressive prostate tumors accumulate lipid droplets to fuel tumor metastasis. Recently, high-fat diet has been shown to rapidly promote tumor metastasis in the otherwise non-metastatic Pten-knockout mouse model. Key regulators of fat synthesis by the tumor cells and lipid uptake from the tumor microenvironment may be important targets for therapeutic intervention to prevent/inhibit PC metastasis. HOXB13 is a DNA-binding protein specifically expressed in the prostate and essential for normal prostate development. HOXB13 continues to express at high levels in adult prostate and regulates prostatic gene expression. In preliminary studies, we observed gradual loss of HOXB13 expression from primary PC to mHSPC and to mCRPC associated with DNA hypermethylation. We identified a metastasis-inhibiting function of HOXB13 by suppressing de novo lipogenesis and lipid uptake. This is mediated by a novel protein interaction between HOXB13 and the histone deacetylase 3 (HDAC3), an enzyme that removes histone acetylation (e.g. H3K27ac) at lipogenic genes to inhibit their expression. Interestingly, this interaction is disrupted by HOXB13 G84E mutation that has been reported in 4.7% familial PC. Accordingly, in PC cells with either HOXB13 loss or G84E mutation, there are greatly increased H3K27ac and recruitment of CBP/p300, enzymes that catalyze H3K27ac and oppose HDAC3, at lipogenic genes. Accordingly, these cells exhibit high levels of lipid accumulation and strong cell motility. All of these can be fully blocked by small molecule inhibitors of CBP/p300 (p300i). We hypothesize that HOXB13 loss marks a subtype of metastasis-initiating PC that have increased dependency on CBP/p300 for lipogenesis and cellular energy and thus have higher sensitivity to clinically available p300i such as CCS1477. 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 HSPC and CRPC samples, and determine its correlation with tumor metastasis, disease progression, clinical outcomes and related genetic events. Aim 2 will investigate whether molecular and pharmacological inhibition of CBP/p300 abolishes HOXB13 loss-induced lipid gene expression, lipid accumulation, and cell motility. Finally, Aim 3 will evaluate whether HOXB13 loss-of-function sensitizes PC to a clinically available CBP/p300 inhibitor CCS1477, focusing cell motility in vitro and tumor metastasis in xenograft models. Ultimate Applicability of the Research: The present study will address two Overarching Challenges: (1) develop treatments that improve outcomes for men with lethal PC and (2) define the biology of lethal PC to reduce death. Results from Aim 1 will inform the potential of HOXB13 down-regulation as a biomarker for PC metastasis or progression. This will be further tested within 2 years in a prospective clinical study of mHSPC patients receiving first-line ADT/ARPi to assess HOXB13 expression and methylation changes following treatment and its association with disease progression. We are presently in discussions with CellCentric for collaboration on CCS1477. They have expressed a strong interest in selection biomarkers for CCS1477. Resu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210125
Entities
People
- Jindan Yu
Organizations
- Northwestern University
- United States Army