Project 2: Overcoming Microenvironment-Mediated Resistance to AR Pathway Inhibition in High-Risk Prostate Cancer

ABSTRACT/SUMMARY The majority of prostate cancers are dependent on androgen receptor (AR) signaling across clinical disease states. While initially approved for patients with metastatic castration-resistant prostate cancer, recent phase III trials have shown that second-generation AR pathway inhibitors (abiraterone acetate, enzalutamide, apalutamide, darolutamide) convey even greater benefit when used earlier in the disease course in patients with metastatic hormone-sensitive and non-metastatic castration-resistant prostate cancer. Indeed, this concept has also extended to the neoadjuvant treatment of patients with locally advanced high-grade primary prostate cancer. However, despite potent AR inhibition, complete pathologic response rates have remained low. Thus, there is a significant need to further define the mechanisms driving resistance to AR-targeted therapies in this unique context and develop therapeutic strategies that enhance response rates in patients with high-risk localized prostate cancer to shift the treatment paradigm from disease control to cure. Through single-cell RNA sequencing studies of human and mouse prostates, we recently discovered that neuregulin 1 (NRG1) is an AR-regulated gene in normal prostate stromal cells critical to sustaining survival of normal luminal epithelial cells. Parallel studies in prostate cancer preclinical models revealed that stromal- derived NRG1 in the prostate cancer microenvironment promotes cancer cell persistence following AR- targeted therapies. Secreted NRG1 promotes resistance through HER2/3-PI3K/AKT-mediated signaling in prostate cancer epithelial cells. We are now poised to define the NRG1 downstream signaling nodes driving cancer cell persistence to AR targeted therapies and optimize therapeutic strategies targeting the NRG1 axis in combination with AR inhibition. We will investigate the effects of targeting individual nodes of the NRG1- HER2/3-PI3K pathway to overcome resistance to AR-targeted therapies in preclinical trials using clinical-grade inhibitors of NRG1, HER2/3, PI3K, and AKT in combination with AR antagonists. Furthermore, in the proposed project we will take a comprehensive approach to defining the microenvironmental mechanisms contributing to prostate cancer cell persistence after AR-targeted therapy. Using single-cell sequencing technology, we will define the changes in prostate cancer microenvironmental cell populations following AR inhibition and evaluate differential gene expression within these cell populations to identify novel cytokine-receptor pairs contributing to cancer cell persistence in primary and metastatic prostate cancers. Finally, we will conduct a phase Ib/II neoadjuvant clinical trial of PI3K (copanlisib) and androgen-deprivation therapy prior to prostatectomy in patients harboring loss of PTEN, an established mediator of resistance to AR-targeted therapies. Our collective work will set the path for novel precision medicine–based neoadjuvant trials to improve the cure rates of men with high-risk localized prostate cancer.