Development of PARP Inhibitors and DDR Modifiers To Treat Ovarian Cancer

The nuclear enzyme poly-(ADP-ribose) polymerase 1 (PARP1) plays a critical role in several different DNA repair pathways.

Previous work from other laboratories showed that PARP inhibitors are particularly toxic to cells with defects in the homologous recombination (HR) repair pathway, including breast and ovarian cancer cells with deleterious BRCA1 or BRCA2 mutations.

Building on these observations, Dr. Kaufmann's lab has been trying to understand the unique susceptibility of HR-deficient cancer cells to PARP inhibitors and to identify and test combinations with other agents that might extend the benefit of PARP inhibitors to additional types of cancer.

Our lab's major findings have included:

  • Realization that iniparib, an agent brought to the clinic as a PARP inhibitor, was not a PARP inhibitor after all. These observations facilitated the restart of PARP inhibitor trials that had been paused after negative clinical results with iniparib were announced.
  • Demonstration that PARP inhibitors activate the error-prone nonhomologous end-joining (NHEJ) pathway in cells with HR defects, leading to chromosomal rearrangements that contribute to PARP inhibitor-induced cell death.
  • Observation that loss of RAD51C gene methylation contributes to PARP inhibitor resistance in RAD51C-methylated ovarian cancer, along with the striking observation that as few as 1 cell in 6,000 with unmethylated RAD51C can cause resistance within months.
  • Demonstration that PARP inhibitors sensitize ovarian cancer cells with either wild type or mutant BRCA1/BRCA2 proteins to the topoisomerase I poison topotecan and the ATR kinase inhibitor berzosertib. Importantly, this sensitization reflects trapping of PARP1 on damaged DNA, preventing proper repair after topoisomerase I-mediated events. These observations have led to a series of clinical trials.