Identification of Therapeutic Vulnerability in Prostate Cancer Harboring Chromosome 17p Loss
Abstract
Prostate cancer is among the most common male malignancies and one major leading cause of cancer mortality in men. Since the discovery of androgen dependence in prostate cancer, androgen deprivation is the mainstay of therapy for advanced prostate cancer treatment. Despite initial responses, almost all patients progress to castration-resistant prostate cancer (CRPC). There are only a few medications registered for the treatment of CRPC at this time, and they are often associated with drug resistance and cancer relapse/recurrence. Hence, it is of urgent need and great significance to develop effective treatments for CRPC. Development of novel strategies precisely targeting the genetic alternations is valuable for fighting against CRPC. Partial loss of human chromosome 17p (Chr17p) is one of the most frequent genomic events that contribute to prostate tumorigenesis. Beyond the tumor suppressor TP53, whose deletion or mutation has been long known as a primary tumorigenic driver, the biological and clinical consequences of those co-deleted genes in the Chr17p region remain to be fully elucidated. A tremendous effort has been made to restore p53 activity in cancer therapies. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment. We identified a novel drug target gene, POLR2A, which is included in the deletion region of Chr17p of 63% of metastatic CRPC. Inhibiting POLR2A with small compound drug a-amanitin selectively inhibits proliferation, survival, and the tumorigenic potential of CRPC cells with partial loss of Chr17p. Previous clinical applications of a-amanitin have been limited due to its liver toxicity. We found that a-amanitin-based antibody drug conjugates (ADCs) are highly effective therapeutic agents with significantly reduced toxicity. PSMA (prostate-specific membrane antigen) is a membrane-bound glycoprotein and is frequently overexpressed in CRPC cells. PSMA antibody is a fully humanized antibody. We will develop and optimize a-amanitin-based ADC using this antibody and demonstrate that a-amanitin-conjugated ADC is a specific and effective drug for the treatment of CRPC with partial loss of Chr17p. We will evaluate the therapeutic efficacy of this ADC in the preclinical prostate cancer models. Three specific aims are: Aim 1. To investigate the mechanism of drug resistance in the CRPC harboring partial loss of Chr17p. Aim 2. To develop and optimize the synthesis of anti-PSMA conjugated a-amanitin. Aim 3. To determine the in vivo anti-cancer activity of anti-PSMA a-amanitin conjugates in the preclinical mouse model of CRPC. Given the limited therapeutic options for CRPC, our findings identified potential drug targets from a common Chr17p deletion event in human CRPC. This project will demonstrate that partial loss of Chr17p in human prostate cancer confers therapeutic vulnerabilities, which can be utilized to develop novel targeted cancer therapy for CRPC. The project will address the overarching challenge, “developing treatments that improve outcomes for men with lethal prostate cancer.” The short-term goal of this project is to demonstrate anti-PSMA-a-amanitin conjugates as a novel targeted therapy for p53-defective CRPC. Our long-term goal is to take advantage of the clinical resources at Indiana University’s Simon Cancer Center to initiate an Investigational New Drug application.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010201
Entities
People
- Xinna Zhang
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army