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Making the best of PARP inhibitors in ovarian cancer

Abstract

Drugs that inhibit the enzyme poly(ADP-ribose)polymerase (PARP) are showing considerable promise for the treatment of cancers that have mutations in the BRCA1 or BRCA2 tumor suppressors. This therapeutic approach exploits a synthetic lethal strategy to target the specific DNA repair pathway in these tumors. High-grade ovarian cancers have a generally poor prognosis, and accumulating evidence suggests that mutations in BRCA1 or BRCA2, or silencing of BRCA1 by promoter methylation, may be common in this disease. Here, we consider how the potential benefit of PARP inhibitors might be maximized in ovarian cancer. We suggest that it will be crucial to explore novel therapeutic trial strategies and drug combinations, and incorporate robust biomarkers predictive of response if these drugs are to reach their full potential.

Key Points

  • Defects of the BRCA pathway are common in high-grade serous ovarian cancer

  • The enzyme poly(ADP-ribose)polymerase (PARP) is a critical component of the base-excision-repair pathway

  • A synthetic lethal interaction exists between PARP inhibition and BRCA1 or BRCA2 mutations

  • PARP inhibitors are showing promising results in preclinical and clinical trials for the treatment of BRCA-deficient cancers

  • Consideration needs to be given to the optimal use of these drugs in ovarian cancer

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Figure 1: Mechanism of synthetic lethality between BRCA deficiency and PARP inhibition.
Figure 2: Effects of PARP inhibition on BRCA2-mutant cells.
Figure 3: CT scans of two patients with advanced ovarian cancer.

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Acknowledgements

We thank Breakthrough Breast Cancer and Cancer Research UK for funding.

Charles P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

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S. Banerjee, S. B. Kaye and A. Ashworth contributed to discussion of content for the article, researched data to include in the manuscript, reviewed and edited the manuscript before submission, and revised the manuscript in response to the peer-reviewers' comments.

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Correspondence to Alan Ashworth.

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A. Ashworth is a patent holder/applicant in association with the Institute of Cancer Research and AstraZeneca Rewards to Inventors Scheme. S. B. Kaye is on advisory boards for AstraZeneca and Merck. S. Banerjee declares no competing interests.

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Banerjee, S., Kaye, S. & Ashworth, A. Making the best of PARP inhibitors in ovarian cancer. Nat Rev Clin Oncol 7, 508–519 (2010). https://doi.org/10.1038/nrclinonc.2010.116

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