Exploring the Role of Ferroptosis as a Tumor-Intrinsic Molecular Determinant of Bipolar Androgen Therapy
Abstract
Androgen deprivation therapy (ADT) is the backbone of treatment for lethal recurrent and metastatic prostate cancer (PCa). Although the initial response rate to ADT is high, the 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, my research group has treated 330 patients across four Phase II studies using SupraT administration, also known as bipolar androgen therapy (BAT), documenting safety as well as significant clinical efficacy in a subset of men with mCRPC patients. Understanding how SupraT works at the cellular and molecular levels might help in rationally combining BAT with other agents to achieve increased efficacy and tumor responses. The proposed work will have a long-term impact on two DOD overarching challenges for early investigator research award 2021: (1) develop treatments that improve outcomes for men with lethal prostate cancer and (2) define the biology of lethal prostate cancer to reduce death. Our goal is to understand and define the molecular features of the tumors that respond dramatically to BAT. The present proposal is important, as it will provide valuable clinical insights that can be utilized to select patients who would respond to the therapy and provide prognostic markers for BAT therapy. Our data indicate that SupraT treated PCa cells accumulate lipid peroxides and undergo a specialized death called ferroptosis. Lipid peroxides induced by SupraT activate NF-kappaB (an important immune regulator) to induce an innate immune response. The result of this process is the activation of innate immune cells called natural killer (NK) cells that home in and destroy the tumor cells. In the proposed work, I will rigorously test my hypothesis that (1) SupraT induces ferroptosis mediated cell death; (2) prostate cancer cells that have DNA repair defects are more prone to ferroptotic cell death; and (3) ferroptosis activates the NF-kappaB pathway and alerts the immune system to destroy prostate cancer cells. I will test this hypothesis in cellular and patient tumor-derived animal models. My research group has an ongoing BAT clinical trial at Hopkins, and I will obtain tumor biopsies from patients on this trial to test whether: (1) ferroptosis is activated by BAT therapy; (2) patients having DNA repair defects in their tumors have increased activation of ferroptosis pathway; and (3) the innate immune cells are activated and attracted towards the tumors with an intent to kill in response to BAT therapy. I will work with a team of experts, including a biologist, a translational oncologist, and a tumor immunologist. They are experts in the area of cell and molecular biology, prostate cancer clinical studies, animal cancer models, and tumor immunology. They will provide their expertise to achieve this common goal. This is the first such study to prospectively assess ferroptosis activation as a biomarker of response to BAT therapy in prostate cancer. Most importantly, this proposal aims to study a never-before-tested idea with a potential transformative (rather than incremental) impact on the field. I hope that insights gained after the successful completion of the project will help us offer BAT therapy in an informed manner and help us devise strategies and seamlessly translate our laboratory findings to a larger cohort of advanced metastatic prostate cancer patients after completing our project proposal. I have chosen my mentors to guide me through the proposed work, and each one is a leader in their respective field with complementary skills. Dr. Sushant Kachhap, who serves as my primary mentor, has a strong
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210118
Entities
People
- Rajendra Kumar
Organizations
- Johns Hopkins University
- United States Army