Innate Immune Signaling Induced by Androgens: Implications in Tumor Response to Bipolar Androgen Therapy
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 Johns Hopkins studying the paradoxical effects of supraphysiologic testosterone (SupT) 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 II studies using bipolar androgen therapy (BAT), documenting safety as well as significant clinical activity in a subset of men with mCRPC. 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 that can then be utilized for future selection of patients who would respond to the therapy and provide biomarkers for response to therapy. In the past, we and others have reported that SupT causes breaks in DNA. It is speculated that unrepaired DNA breaks may lead to cellular crisis and the death of prostate cancer cells. In our published and unpublished data, we have observed an association between tumors harboring DNA-repair defects and favorable responses to BAT, likely through a mechanism of BAT-induced DNA damage. In search for a mechanism, we have uncovered a novel pathway by which damaged DNA induced by SupT are shuttled outside the nucleus into the cytoplasm and enclosed in tiny vesicles called autophagosomes for subsequent degradation through a process called nucleophagy. Normally, DNA is present inside the nucleus and does not come in direct contact with the cytoplasm. Cytoplasm harbors DNA sensors that safeguard cells against pathogenic DNA (from bacteria and viruses) by triggering an innate immune response. Our data indicate that SupT-induced damaged DNA is able to activate cytoplasmic sensors (specifically, the cGAS-STING pathway) and induce an innate immune response. The result of this process is activation of innate immune cells called natural killer (NK) cells that home in and destroy the tumor cells. In the proposed work, we will rigorously test our hypothesis that (1) SupT induces nucleophagy-mediated degradation of damaged DNA; (2) nucleophagic degradation of damaged DNA is more pronounced in prostate cancer cells that have DNA repair defects, and (3) nucleophagy alerts the cGAS-STING pathway dependent innate immune system to destroy prostate cancer cells. We will test our hypothesis in cellular and patient tumor animal models. We have an ongoing BAT clinical trial at Johns Hopkins and will obtain tumor biopsies from patients in this trial to test: (1) whether cGAS-STING is activated by BAT therapy, (2) whether patients having DNA repair defects in their tumors have increased activation of the cGAS-STING pathway, and (3) whether the innate immune cells are activated and are attracted towards the tumors with an intent to kill in response to BAT therapy. We have assembled a team of translational oncologists, a prostate cancer molecular biologist and a cell biologist who are expert in animal cancer models, and tumor immunologists who will provide their complementary expertise in accomplishing our common goal. This is the first study to prospectively assess DNA damage and STING activation 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 can
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910724
Entities
People
- Sushant K. Kachhap
Organizations
- Johns Hopkins University
- United States Army