Investigating Noncanonical Roles of Androgen Receptor in Driving Growth Inhibition by Supraphysiological Androgen in Prostate Cancer
Abstract
Prostate cancer is the most common cancer in men. Androgens drive prostate cancer growth by binding to its receptor, known as the androgen receptor. Inhibiting androgen receptor signaling by androgen deprivation therapy (ADT) is the first line of therapy for prostate cancer. Initially, all patients respond, but later develop resistance to therapy. Once the castration resistance develops in patients, cancer advances further and is called metastatic castration-resistant prostate cancer. Bipolar androgen therapy (BAT) is a paradoxical approach that involves the administration of supraphysiological doses of testosterone (SupraT), which has been shown to dramatically decrease growth in a subset of prostate cancer cases. It involves the cycling of androgen levels between supraphysiological high and castration values. Patients in early trials of BAT showed promising clinical responses. Despite favorable outcomes in preclinical and clinical subjects, not all patients show clinical benefits and differ in the extent and duration of response. Also, the mechanism of action of BAT is not fully known and could be responsible for partial clinical success. Multiple studies are being conducted to understand how BAT works, and many researchers have reported partial success. This proposal aims to study a never-before-tested idea with a potential transformative (rather than incremental) impact on the field. In this exploration hypothesis development award, we will test the hypothesis that androgen receptor in the presence of SupraT leads to androgen receptor aggregates in the prostate cancer cells, very similar to that reported in Kennedy disease, a disease condition where an individual inherits mutated androgen receptors. These aggregates would result in a stressful cellular condition called ER stress that would lead to the death of prostate cancer cells. We further postulate that prostate cancer cells that are unable to handle the ER stress would be most susceptible to SupraT administration and BAT. We propose to explore this vulnerability by combining SupraT with clinical drugs that are known to cause ER stress. Our idea is that a combination of SupraT and ER stressor will overwhelm the ER stress pathway to cause prostate cancer cell death and inhibit growth, even in those subsets that do not respond favorably to BAT. Our aims are structured to test the hypothesis in prostate cancer cell lines and patient-derived organoid models that closely resemble original prostate tumors. The proposed work will directly impact PCRP s FY22 Overarching Challenge, develop treatments that improve outcomes for men with lethal prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310029
Entities
People
- Rajendra Kumar
Organizations
- Johns Hopkins University
- United States Army