Developing Strategies to Overcome Prostate Stromal-Derived NRG1-Mediated Resistance to AR Blockade in High-Risk Locally Advanced Prostate Cancer
Abstract
High-grade locally advanced prostate cancer occurs in approximately 30% of newly diagnosed patients and represents a therapeutic challenge as greater than 60% of patients will recur and progress following radical prostatectomy or radiation therapy. To improve clinical outcomes for men with high-risk localized prostate cancer, several clinical trials have evaluated the role of complete androgen blockade prior to prostatectomy. Despite ongoing enthusiasm for this approach, complete pathologic response rates (a marker for therapeutic efficacy) is only observed in 4 to 10% of patients. Through preclinical studies, we have recently discovered, for the first time, that the prostate cancer microenvironment stromal cells secrete neuregulin (NRG1) in response to androgen blockade, which promotes the cancer cells to survival an androgen-deprived state. Our recent finding explains in part why so few high-risk primary prostate cancers achieve a complete pathologic response to androgen blockade. Importantly, the neuregulin signaling pathway is therapeutically actionable with several clinical agents either FDA-approved for other malignancies or in early development. Our research proposal aims to define the downstream mechanisms through which NRG1 promotes cell survival and determine the therapeutic strategies targeting the NRG1 pathway that enhance response to androgen blockade. In collaboration with Dr. Anuradha Gopalan (pathologist), we have established an immunohistochemical protocol for evaluating NRG1 expression in primary prostate cancer. We have designed studies to define the prevalence of NRG1 expression in high-risk localized prostate cancer following AR inhibition and correlate NRG1 expression with clinical and pathologic response. This work could lead to NRG1 expression as a biomarker of response/resistance to androgen blockade. Our studies are responsive to the overarching challenge of improving survival for me with high-risk localized prostate cancer. Our work has the potential to improve our understanding of how the cancer environment influences resistance to androgen blockade and lead to novel combination therapies vastly changing the standard of care for men with high-risk prostate cancer. Working closely with Dr. Dana Rathkopf (medical oncologist), we are positioned to develop a neoadjuvant clinical trial (Phase Ib/II) for high-risk primary prostate cancer combining AR and NRG1 pathway inhibition prior to prostatectomy within the next 2 years. Through this work, we aim to dramatically improve the cure rates for men with high-risk localized prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110431
Entities
People
- Brett Carver
Organizations
- Sloan-Kettering Institute
- United States Army