The Role of Androgen Receptor and Chromatin Binding Proteins in Mediating the Testosterone Paradox
Abstract
Androgen deprivation therapy (ADT) is the backbone of treatment for recurrent and metastatic prostate cancer. Although the initial response rate to ADT is high, progression inevitably develops leading to a clinical state of castration resistance. Through the pioneering preclinical and clinical work at Hopkins studying the paradoxical effects of supraphysiologic testosterone (SupraT) in prostate cancer, we have discovered a novel therapeutic strategy using high-dose (supraphysiological levels) testosterone as a treatment for metastatic castrate-resistant prostate cancer (mCRPC). To date, our group has treated 330 patients across four phase 2 studies using bipolar androgen therapy (BAT), documenting safety as well as significant clinical activity in a subset of men with mCRPC patients. Our goal is to understand and define the molecular features of the tumors that respond dramatically to BAT therapy. This is important as it will provide valuable clinical insights which can then be utilized for future selection of patients who would respond to the therapy and provide biomarkers for response to therapy. We have recently published a finding that suggest that BAT is able to activate immune system in patients who respond to BAT. Activation of immune cells is highly sought in prostate cancer, as prostate cancer is refractory to immunotherapy since immune cells do not infiltrate tumors and kill prostate cancer cells. We intend to find the molecular underpinnings of immune activation by BAT. This will allow us to find novel biomarkers that could predict which patients will respond to BAT. In our preliminary studies, we have found that androgen receptor (AR) activity in prostate tumors dictates response to BAT. Understanding how AR functions in response to BAT can provide insights about why certain tumors respond dramatically to BAT. We will employ an innovative labeling strategy to isolate and identify key regulators of AR function in prostate cancer. This strategy would explain how AR reprograms the genes in response to BAT to bring about growth inhibition and immune cell activation. Thus, enabling us to uncover novel protein markers of BAT response which can be used to stratify which patients will respond to BAT and also to combine BAT with immune therapeutics to achieve better therapeutic outcome. We have assembled a team of translational oncologists, prostate cancer molecular and cell biologist who are expert in animal cancer models, and tumor immunologists who would provide their complementary expertise in accomplishing our common goal. This is the first study to prospectively assess AR modulators as biomarkers of response to BAT therapy in prostate cancer. Most importantly, this proposal aims to study a never-before tested idea with potential transformative (rather than incremental) impact on the field. We hope that insights gained after successful completion of the project will help us offer BAT therapy in an informed manner and help us devise strategies to provide benefit of the therapy to a larger cohort of advanced metastatic prostate cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310105
Entities
People
- Sushant K. Kachhap
Organizations
- Johns Hopkins University
- United States Army