/NARRATIVE Metastatic prostate cancer (mPC) is a lethal disease with essentially no curative therapy. However, in unselected patients, widely divergent responses to conventional and experimental therapeutics are routinely observed, with occasional ?outlier? or ?exceptional? responders exhibiting durable complete responses and others exhibiting immediate disease progression. This diversity suggests that underlying biological mechanisms accounting for treatment responses can be identified and exploited to prioritize specific therapeutics predicted to have benefit and avoid treatments predicted to lack activity. The genomic landscapes of mPC demonstrate that a substantial fraction of mPC tumors harbor somatic defects in DNA repair genes (DRGs) including BRCA1, BRCA2, ATM, MSH2/6 and others. This finding has important treatment ramifications as a substantial body of preclinical and clinical work indicates that particular types of DNA repair deficiency, particularly Homology Directed Repair (HDR) Deficiency (HDR-D) result in heightened vulnerabilities to at least two drug classes: platinum (PLAT) chemotherapy and PARP inhibitors (PARPi). Also of importance, tumors without a HDR-D genotype/phenotype are less responsive to these drugs. In this proposal we will test the hypothesis that specific aberrations (germ-line or somatic) in genes involved in repairing DNA strand breaks by HDR are predictive of meaningful clinical responses to FDA-approved genotoxic therapeutics and drugs that impair mechanisms of repairing DNA. We will also determine if rational combinations of novel therapeutics targeting DNA repair processes or inducing DNA damage in cancers with HRD will bypass or overwhelm resistance pathways. We have 3 aims:
Specific Aim 1 : Conduct Phase 2 clinical trials of genotoxic therapeutics in patients with mCRPC to determine response rates, identify resistance mechanisms, and establish associations between specific HDR genomic defects and the depth and duration of clinical responses.
Specific Aim 2 : Evaluate rational combinations of pharmacological agents targeting DNA repair pathways using Patient Derived Xenograft (PDX) models of mCRPC with inherent or engineered HDR aberrations.
Specific Aim 3 : Develop minimally-invasive biomarkers involving the capture and analysis of circulating tumor DNA capable of distinguishing patients for therapeutics targeting DNA repair pathways.
The importance and relevance of this project centers on developing a new standard of care involving a targeted therapy for DNA repair deficient prostate cancer, to reduce the morbidity and mortality attributable to advanced prostate cancer and motivate studies designed to use individualized approaches to prioritize therapeutics likely to have substantial benefit in specific patient populations.
Showing the most recent 10 out of 400 publications
