Genetic and Genomic Determinants of Homologous Recombination Repair Deficiency as Treatment Selection Markers for Lethal Prostate Cancer
Abstract
It has recently become apparent that many prostate cancers are driven by inherited genetic abnormalities (called germline DNA mutations) or tumor-specific abnormalities (called somatic DNA mutations) in genes that normally promote repair of DNA damage that is caused when cancer cells divide. The most important process that is responsible for fixing such DNA damage is the “homologous recombination” pathway, composed of several genes, the most well-known of which are BRCA1, BRCA2, and ATM. Prostate cancers with either inherited or tumor-specific (i.e., acquired) mutations in such genes are known as “homologous recombination deficient” (HRD) cancers. Such prostate cancers may need to be treated differently from the rest, and recent studies have suggested that a new class of drugs called poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib and rucaparib, are particularly effective in treating HRD cancers. We hypothesize that, in addition to PARP inhibitors, patients with HRD prostate cancer may do better with other therapies too, namely the novel (but rapidly becoming standard) hormonal therapies (abiraterone and enzalutamide). Identifying standard therapies that may work well against HRD cancers is very important, since PARP inhibitors are not yet approved by the Food and Drug Administration (FDA) for prostate cancer and cannot routinely be used outside of a clinical trial. Also, PARP inhibitors may have worse side effects than standard abiraterone and enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC). Therefore, identifying other therapies that HRD-positive prostate cancer patients may or may not respond to is an important objective of this work. An equally important objective is to confirm our preliminary data that such patients with HRD mutations respond particularly poorly to taxane chemotherapies. Importantly, since this project ultimately aims to help clinicians better select among existing, commonly prescribed front-line therapies for patients with mCRPC (AR-targeting versus taxane therapies), its success does not hinge upon theoretical and unknown timeframe approval of investigational drugs such as PARP inhibitors or other experimental agents. Current methods to detect HRD mutations require tumor biopsies, which can often be technically difficult (especially in bone), painful, and have significant risks. The goal of this proposal is to develop a blood-based method (which we call a “liquid biopsy”) to assess HRD in order to eventually replace needle biopsies. In addition, we will aim to study both the germline (inherited) DNA and the somatic (tumor) DNA using a simple blood test. Finally, on a more technical level, we will try to understand how prostate cancers differ, depending on whether the HRD mutation is inherited versus acquired and whether these two types of cancers (with inherited versus tumor-only HRD mutations) respond differently to novel hormonal therapies and taxane chemotherapies. In summary, the proposed work creates a roadmap for clinical translation enabled by blood-based “liquid biopsies” in a population facing difficult treatment decisions. Also, our effort in defining the impact of mutation status in a well-characterized cohort of mCRPC patients receiving FDA-approved front-line mCRPC therapies, including abiraterone/enzalutamide and taxane chemotherapies, may lead to more effective treatment selection strategies (in other words, it is possible that HRD-positive prostate cancers are better treated with novel hormone therapies and worse with chemotherapies). The proposed work is novel because the molecular signatures in men with and without HRD mutations remain poorly defined. Very importantly, this work may confirm that HRD prostate cancers respond more favorably to novel hormonal therapies and that such patients may not necessarily need immediate treatment with taxanes or PARP inhibitors (or platinum chemotherapy agents), which carry great
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910686
Entities
People
- Jun Luo
Organizations
- Johns Hopkins University
- United States Army