Novel Determinants of PARP Inhibitor Sensitivity in Ovarian Cancer

In this research project, investigators in the Mayo Clinic Ovarian Cancer SPORE are assessing biomarkers of response in both mutant and wild-type BRCA1 and BRCA2 ovarian cancers.

Poly (ADP-ribose) polymerase inhibitors (PARPis) have shown promising activity in homologous recombination (HR)-deficient preclinical models. They have also shown response rates of 30% to 60% in BRCA1 or BRCA2 (BRCA1/2) mutation carriers with platinum-sensitive relapsed ovarian cancer.

These results led to regulatory approval of the PARPi olaparib for ovarian cancer in the U.S. and Europe. In addition, 20% to 30% of ovarian cancers without BRCA1/2 mutations also respond.

But it's unclear how to best identify patients whose ovarian cancer might respond to these agents.

In this project, our investigators are assessing biomarkers of response in both BRCA1/2-mutant and BRCA1/2-wild-type ovarian cancers to help identify these patients.

This project builds on our team's previous results, which showed:

  • Downregulation of nonhomologous end-joining (NHEJ) repair pathway proteins markedly diminishes PARPi sensitivity in vitro
  • BRCA2-mutant ovarian cancer clones selected for PARPi resistance exhibit marked changes in certain repair proteins
  • A number of repair proteins show highly variable expression in pre-treatment samples of BRCA1/2-mutant ovarian cancers

Our researchers are examining the relationship between differences in repair protein expression and PARPi resistance in preclinical studies and in pretreatment biopsies from the phase 2 ARIEL2 clinical trial of single-agent rucaparib in patients with platinum-sensitive, relapsed ovarian cancer.

Assays in the clinical samples are designed to test four complementary explanations for PARPi resistance, including reversion mutations in BRCA1/2, low NHEJ pathway protein expression, variation in PARP1 levels, and compensatory changes in other DNA repair pathways.

This rucaparib study was specifically designed to enroll participants with both BRCA1/2-mutant and BRCA1/2-wild-type ovarian cancers in an attempt to better understand the determinants of response in both groups.