Investigating PTGES3 as a novel therapeutic target in advanced prostate cancer

The National Institutes of Health National Cancer Institute awarded Fred Hutchinson Cancer Center $736,383 on August 1, 2026, under the Cancer Treatment Research program (CFDA 93.395) to investigate PTGES3 as a novel therapeutic target in advanced prostate cancer resistant to androgen receptor signaling inhibitors.

The research addresses mechanisms by which prostate cancer escapes treatment with FDA-approved AR signaling inhibitors through AR reactivation. Fred Hutchinson will conduct biochemical and structural assays to investigate how PTGES3 regulates androgen receptor protein levels, evaluate PTGES3 overexpression in clinical samples to establish it as a biomarker for identifying patients requiring treatment intensification, and develop PTGES3 inhibitors as next-generation therapeutics. The work builds on the recipient's preliminary genome-scale CRISPR screens identifying PTGES3 as a druggable AR protein regulator in aggressive prostate cancer cell models.

The award is structured as a Project Grant with a period of performance from August 1, 2026, through July 31, 2031. Work is performed in Seattle, Washington.

Abstract

The androgen receptor (AR) is a central driver of prostate cancer. The majority of prostate cancers (PCA) express AR throughout the course of the disease, and AR has been shown to promote transcriptional programs governing critical oncogenic phenotypes, such as cancer cell proliferation, migration, and invasion. Accordingly, FDA approved AR signaling inhibitors (ARSI), such as enzalutamide and apalutamide, are now the standard of care for many aggressive PCA patients including metastatic castration-resistant prostate cancer (MCRPC). Problematically, aggressive PCA frequently escape these therapies by reactivating AR signaling through multiple mechanisms including AR mutation, gene amplification, enhancer amplification and splice variants, all of which result in increased expression or activity of the AR protein. Therefore, identifying novel approaches that block AR protein expression represents a promising approach to overcoming all of these mechanisms of resistance in ARSI therapy-resistant MCRPC. We hypothesize that identifying genes required for AR protein levels through genetic screening could yield new strategies for targeting AR-driven prostate cancers resistant to arsis. In our preliminary data, we have identified PTGES3 as a druggable AR protein regulator through genome-scale crispri screens using a novel endogenous AR reporter PCA cell model. We validated that PTGES3 promotes AR levels and activity in multiple aggressive PCA models. We now propose: 1) to investigate the mechanisms by which PTGES3 regulates AR using biochemical and structural assays, providing the foundation for novel anti-PTGES3 and AR-directed prostate cancer therapeutics. 2) to evaluate PTGES3 overexpression in clinical samples and establish IT as a biomarker to identify patients needing early treatment intensification beyond standard arsis. 3) to develop PTGES3 inhibitors as next-generation agents for MCRPC. We have already discovered a first-in-class PTGES3 inhibitor, RAC-18, which selectively inhibits AR-driven MCRPC cell growth and tumor xenografts. We will further optimize and characterize PTGES3 inhibitors in vitro and evaluate their activity in vivo. By investigating PTGES3 in vitro and in vivo from mechanistic, biomarker, and therapeutic perspectives, this study will elucidate the biology of the PTGES3-AR interaction and lay the groundwork for novel therapeutics targeting advanced PCA. Ultimately, this research will enhance our understanding of ARSI-resistant prostate cancers and provide translatable tools for clinical management of patients with this disease.