Development of PARP Inhibitors for the Treatment of Ovarian Cancer and Chronic Leukemias
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 Anticancer Drug Action 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 include:
- Demonstration that PARP inhibitors activate the error-prone nonhomologous end-joining (NHEJ) pathway, leading to chromosomal rearrangements that contribute to PARP inhibitor-induced cell death. Importantly, cells that have lost the NHEJ pathway are resistant to PARP inhibitors, providing an opportunity to potentially better identify individual tumors that are PARP inhibitor sensitive versus resistant. Based on these results, Dr. Kaufmann's laboratory is testing a potential predictive biomarker of PARP inhibitor resistance in samples from several different ovarian cancer trials that employ PARP inhibitors.
- 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 VE-821. Importantly, this sensitization reflects trapping of PARP1 on damaged DNA, preventing proper repair after topoisomerase I-mediated events. These observations have led to a phase I/II clinical trial of the topotecan-veliparib combination in relapsed ovarian cancer and efforts to test the hypothesis that the most sensitive tumors will, in addition to BRCA1 or BRCA2 mutations, have high levels of the enzymes topoisomerase I and PARP1.
- In collaboration with the laboratory of Keith Pratz at Johns Hopkins University School of Medicine, Dr. Kaufmann's laboratory has demonstrated that certain chronic myeloid neoplasms, particularly chronic myelomonocytic leukemia, have defects in the HR pathway that render them particularly sensitive to PARP inhibitors. While more experiments are underway to better understand the biochemical mechanism of this unique vulnerability, PARP inhibitors are being tested in chronic myelomonocytic leukemia and related disorders alone and in combination with DNA-damaging chemotherapy. The goal of these clinical trials and the associated laboratory studies is to better identify individual cancers and leukemias that are particularly susceptible to PARP inhibitor-containing therapy and extend the use of PARP inhibitors beyond just BRCA1 and BRCA2 mutant ovarian cancer.