Examining the mechanisms of response to anti-androgen therapies in aggressive genitourinary cancers

The National Institutes of Health National Cancer Institute awarded Clark Atlanta University, Inc., $194,929 on July 1, 2026, under the Cancer Research Manpower program (CFDA 93.398) to examine the mechanisms of response to anti-androgen therapies in aggressive prostate cancer.

The project investigates why patients with aggressive prostate cancer initially respond strongly to androgen deprivation therapy (ADT) but ultimately develop resistance and progress to castration-resistant prostate cancer (CRPC). The research builds on analysis of primary prostate cancer specimens from a phase II clinical trial of intense neoadjuvant ADT in patients with locally advanced prostate cancer. By examining genomic and transcriptomic features, the research identifies residual cancer burden as a surrogate for progression-free survival and stratifies patients into exceptional responders versus incomplete or non-responders. Preliminary findings highlight overexpression of HER2 in poorly responding tumors with low androgen receptor signaling and overexpression of the tumor suppressor phosphatase INPP4B in exceptional responder samples. The award funds two research objectives: determining the mechanism underlying HER2-mediated proliferation in an androgen receptor-low environment and identifying how INPP4B phosphatase activity drives ADT response.

Performance occurs in Atlanta, Georgia. The project period runs from July 1, 2026, through June 30, 2029. The Cancer Research Manpower program supports biomedical training opportunities for individuals pursuing careers in basic, clinical, and prevention research relevant to the National Cancer Program.

Abstract

Patients with aggressive prostate cancer initially exhibit strong responses to androgen deprivation therapy (ADT) to block androgen-mediated cell proliferation. However, despite this strong response to ADT, these patients will ultimately develop resistance and progress into castration-resistant prostate cancer (crpc). The mechanisms underlying this response or resistance to ADT in early-stage cancers remain largely unknown. The foundation for this proposal derives from our work examining primary prostate cancer specimens from a phase II clinical trial examining intense neoadjuvant ADT (inadt) in patients with locally advanced prostate cancer who would otherwise be ineligible for surgery. By examining the genomic and transcriptomic features of these tumors at an early stage, we are able to identify new drivers of early-stage prostate cancer progression. We identified residual cancer burden (RCB) after treatment, which serves as a surrogate for overall progression-free survival, and then stratified patients into those who exhibited either exceptional response (ER) or incomplete/non-response (INR). This allows US to examine the genomic and transcriptomic differences between the classes, which led to our central hypothesis that a subset of genetic alterations driving tumorigenesis predispose tumor sensitivity or resistance to ADT. Our preliminary data highlight the egfr family, and specifically HER2, is overexpressed in poorly responding tumors with low androgen receptor (AR) signaling, while the tumor suppressor phosphatase, INPP4B, as significantly overexpressed in ER samples compared to INR to identify mechanisms predisposing prostate tumors to intrinsic response or resistance to inadt, we will determine 1) the mechanism underlying HER2-mediated proliferation in an AR-low environment; and 2) how INPP4B phosphatase activity drives response to ADT. In aim 1, we will examine HER2-mediated signaling to drive prostate cancer proliferation in an AR-low environment. In aim 2, we will determine how INPP4B mediates prostate cancer cell sensitivityadt, both in pten-intact and pten-null tumors. This work will advance our understanding of the mechanisms underlying early stage prostate cancer cell response to ADT, which will provide new insights into potential mechanisms to phenocopy these results to improve overall survival of aggressive prostate cancer.