Defining and Modulating BRCAness to Improve the Precision of Prostate Cancer Therapy
Abstract
Background and Rationale: Metastatic prostate cancers are now recognized to comprise a spectrum of subtypes defined by specific genomic aberrations. One subtype involves mutations in genes that regulate a particular way in which DNA damage is repaired. This process, termed homology-directed DNA repair, or HDR, is regulated by the BRCA1/BRCA2 gene family, which comprises several other members. Defects in these genes provide particular sensitivity to treatments that either induce substantial DNA damage, such as platinum chemotherapy, or that interrupt another DNA repair process, PARP inhibitors. Recently, two PARP inhibitors received Food and Drug Administration approval, specifically for men with tumors that have mutations in BRCA1, BRCA2, and related genes. However, the current biomarkers used to select patients for PARP and platinum therapy are not optimal. Many men currently testing as biomarker-positive fail to respond, whereas the current biomarker panels also exclude subsets of patients who actually will benefit. Further, currently, ~20% of patients with metastatic prostate cancer are likely to benefit from these drugs. Hypotheses/Objectives: This proposal is designed to address two challenges: the first is to improve the accuracy of detecting prostate cancers with HDR defects for appropriate treatment allocation. The second is to increase the number of men with metastatic prostate cancer that could benefit from therapeutics that target DNA repair deficiency be converting partially sensitive tumors into fully sensitive tumors; that is, generating a “BRCAness” phenotype. Specific Aims: Through Aim 1, we will develop and test clinical grade assays that define prostate cancers with functional homology-directed DNA repair deficiency to improve sensitivity and specificity relative to the current gene mutation tests. Through Aim 2, we will identify specific combinations of DNA repair gene and metabolic parameters that underlie a deficiency in DNA repair. Through Aim 3, we will identify pharmacological agents (drugs) that convert tumor cells capable of repairing DNA damage to cells that cannot do so and, thus, render them susceptible to PARP inhibitors or chemotherapy. What is the Contribution to the Overarching Challenges? The research proposed is all directly oriented toward the clinical management of metastatic/advanced prostate cancer. This includes accurately identifying those men with specific DNA repair defects and using this information to direct a specific therapy expected to exploit this specific vulnerability to improve outcomes. The proposal directly addresses two key CDMRP PCRP Challenges: (1) develop treatments that improve outcomes for men with lethal PC and (2) define the biology of lethal PC to reduce death. What Types of Patients Will Benefit and How? Men with metastatic prostate cancer will be the first to benefit. Accurately identifying men most likely to respond to PARP and platinum therapy will ensure that the correct treatment is given and avoid futile treatment for those predicted not to benefit. Further, by converting a non-responsive tumor to a responsive tumor, more men with advanced prostate cancer could benefit from effective PARP therapy and specific chemotherapy. What is the Project Timeline? The assay for accurately identifying men with DNA repair deficiency will be fully tested and deployed for clinical use within the 3-year time frame of this proposal. The results of testing and identify drug combinations potentially capable of inducing DNA repair deficiency will be a continual process with the first results available by the end of year 2 and remainder at the end of year 3. As we are testing drugs with known safety profiles in humans, clinical testing can commence immediately. The research proposed is all directly oriented toward the clinical management of aggressive and advanced prostate cancer. This includes identifying those men with DNA re
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110264
Entities
People
- Peter S Nelson
Organizations
- Fred Hutchinson Cancer Center
- United States Army