Proprietary Arginine Vasopressin Receptor Type 1a (AVPR1a) Antagonists for Treatment of Lethal Prostate Cancer
Abstract
Background and Rationale: Androgen deprivation therapies are initially effective for prostate cancer, but invariably tumors become resistant to this treatment. This disease stage, termed castration-resistant prostate cancer (CRPC), is incurable and new therapeutic approaches are critically needed particularly for metastatic (m)CRPC which has a dismal 30% 5-year survival rate. PC most frequently metastasizes to the skeleton and causes extensive bone damage that greatly contributes to patient morbidity and diminishes the effectiveness of chemotherapies to treat PC. We discovered that a protein, arginine vasopressin receptor type 1a (AVPR1A), is present in highest amounts in human CRPC and metastatic CRPC tumors compared to early-stage tumors. We showed that a safe and effective compound that blocks AVPR1A (tested in human clinical trials for non-cancer disorders) decreased CRPC and, of particular importance, decreased end-stage CRPC growth in the skeleton in mouse models. We published these results in the high impact journal Science Translational Medicine (Zhao et al. 2019). Follow up studies (Heidman et al. 2022 Molecular Cancer Research) extended these findings and also showed that CRPC cells can make the hormone arginine vasopressin (AVP) that activates AVPR1A. This latter finding is of clinical importance because AVP made by CRPC tumors may establish a vicious cycle of perpetual tumor growth (particularly bone mCRPC). Thus, drugs that block AVPR1A may be very effective for mCRPC. Unfortunately, there are no FDA approved AVPR1A blocker drugs and the manufacturer of an existing compound (balovaptan) will not authorize its use for CRPC. With no available FDA-approved antagonists, co investigator Dr. Yangbo Feng, a medicinal chemist, designed and synthesized seven new balovaptan-like compounds for which intellectual property can be established. (Achieving intellectual property rights will facilitate all partnerships necessary for clinical trials.) These compounds performed well as AVPR1A blockers in cell-based experiments. The top two compounds demonstrated excellent drug-like properties in animals. Objective and Aims: Given the success we observed with known AVPR1A blockers in CRPC/mCRPC and the promising drug-like properties of our newly designed compounds, we hypothesize that blocking AVPR1A is a powerful approach for combatting CRPC/ mCRPC. We will test the most promising new AVPR1A blocker in a spectrum of pre-clinical CRPC models (from invasive to metastatic to late-stage growth in bone) to lay the foundation for Investigational New Drug approval and eventual clinical trials. Focusing the expertise of our multi-disciplinary team of scientists, our strategy consists of three highly achievable aims. First, we will complete our pharmacological analysis of the new AVPR1A blockers in animals, to identify the most selective and effective AVPR1A blocker and determine optimal dosing. Second, we will test the lead AVPR1A blocker in a continuum of CRPC models. Specifically, we will evaluate the anti-tumor effects of an AVPR1A blocker both in human CRPC cell lines growing in mouse prostates and in human tumors transplanted to mice (aka, patient-derived xenografts), collectively representing an array of PC features found in men. Third, co-investigator Dr. Conor Lynch’s highly specialized analysis of cancers that metastasize to the skeleton (in mice) will be leveraged to evaluate our top candidate in this devasting end stage of CRPC. These studies will include mice with fully functional immune systems. PCRP Overarching Challenges: In targeting AVPR1A for drug treatment, we advance a therapeutic strategy for those with incurable CRPC/mCRPC, directly addressing the PCRP challenge, Develop treatments that improve outcomes for men with lethal prostate cancer. Patient Applicability: This proposal focuses on treating CRPC/metastatic CRPC with a compound selected for ideal pharmacological properties
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310389
Entities
People
- Kerry L Burnstein
Organizations
- United States Army
- University of Miami