Targeting the Subtype of Metastatic Prostate Cancer Deficient in DNA Repair Capacity
Abstract
Background: Recent work, to which our group contributed, has ascertained the landscape of molecular changes that occur in the genomes of metastatic castration-resistant prostate cancer (mCRPC). Among the important and unanticipated findings was the observation that a high percentage (~20%) of mCRPC tumors have defects in critical genes that are responsible for recognizing and repairing damaged DNA. One detrimental consequence of this defect is the accelerated accumulation of further mutations that drive cancer. A second, but beneficial, consequence of this defect is the exposure of a new vulnerability in the cancer cell, whereby therapies that further promote DNA damage can lead to tumor cell catastrophe and cell death, and therapies that impair other mechanisms used by cells to repair damage will also lead to cell death. Both treatment approaches preferentially damage tumor cells that have lost the repair capacity relative to normal cells that retain the repair capacity. The defective genes in the prostate cancers, BRCA1, BRCA2, and others, are well known to be involved in the hereditary predisposition to other cancers, particularly breast and ovarian cancers. In this context, we also found that a high percentage of men, ~10%, also had germ-line or inherited mutations in these DNA repair genes. This finding has important implications for cancer screening in family members. It also provides an opportunity to rapidly identify men with mCRPC who may benefit from therapies directed toward these DNA repair defects. Hypotheses/Objectives: This proposal aims to address several outstanding questions: 1. Are aberrations (germ-line or acquired in the tumor) in key genes that repair DNA predictive of meaningful clinical responses to specific Food and Drug Administration (FDA)-approved therapies that damage DNA (e.g., carboplatin) and drugs that impair alternative mechanisms of repairing DNA (e.g., PARP inhibitors). 2. Can we determine whether a man’s tumor has a defect in the ability to repair DNA using a blood test, rather than requiring an invasive tumor biopsy. 3. Are there combinations of drugs that can further enhance the killing of tumor cells that are deficient in DNA repair mechanisms and completely eradicate them? Impact: This proposal has the potential to impact men with prostate cancer in at least three major ways. First, determining that prostate cancers possessing DNA repair gene mutations are highly susceptible to specific treatments will provide a precision approach for selecting therapy with a very high likelihood of treatment responses in that selected group of men. Second, determining which gene mutations actually confer substantial responses to specific DNA-damaging treatments will provide more precise and refined recommendations for treatment. Third, developing a non-invasive blood test to determine the genetic/genomic composition of the tumor would avoid the discomfort, risk, and cost of invasive tumor biopsies. It would also provide a highly specific tool for monitoring the responses to cancer therapy over time. The research proposed is directly oriented toward the clinical management of aggressive and advanced prostate cancer. This includes identifying those men with DNA repair defects and using this information to direct a specific therapy expected to exploit this specific vulnerability to improve outcomes. The project has the potential to achieve outcomes that will direct impact patients within the 3-year time span of the proposal.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810356
Entities
People
- Colin C Pritchard
Organizations
- United States Army
- University of Washington