Evaluation of DNA Repair Function as a Predictor of Response in a Clinical Trial of PARP Inhibitor Monotherapy for Recurrent Ovarian Carcinoma
Abstract
The breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2) are key components of the Fanconi anemia (FA)/homologous recombination (HR) pathway of DNA repair. Previous work had shown that cancer cells with deleterious FA/HR pathway mutations are hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Importantly, however, only about half of the cancer patients with germline FA/HR pathway mutations respond to PARP inhibitors, raising the question of why a substantial fraction of HR-deficient cancers are resistant to these agents in the clinic. Based on previous work in the Swisher and Kaufmann laboratories, we proposed to test the hypothesis that two different conditions must be met for ovarian cancer to be hypersensitive to platinum and PARP inhibitors: The FA/HR pathway must remain disabled and NHEJ must remain intact and functional. Although we proposed two aims, the aim in previously banked specimens was removed before the present grant was awarded, leaving us with the following aim: Correlate biomarkers of HR deficiency and NHEJ pathway integrity in pre-treatment biopsies with response to a PARPi in a prospective single-agent PARPi phase 2 clinical trial in sporadic ovarian carcinoma. Over the past 11 months we have i) completed IRB and HRPO review of our project, ii) developed and performed rigorous validation of our IHC assays, and, as of a few weeks ago, iii) begun accessioning samples from the phase 2 rucaparib trial (Ariel 2. ClinicalTrials.gov identifier NCT01891344).
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2014
- Accession Number
- ADA611987
Entities
People
- Scott H Kaufmann
Organizations
- Mayo Clinic