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Veliparib in ovarian cancer: a new synthetically lethal therapeutic approach

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Summary

Epithelial ovarian cancer (EOC) accounts for nearly 90% of all ovarian malignancies. The standard therapeutic strategy includes cytoreductive surgery and neo (adjuvant) platinum-based chemotherapy. Relapse of advanced high grade serous ovarian cancer (HGSOC) is related to the development of drug resistance. A defective DNA damage response is a defining hallmark of HGSOC. Poly (ADP-ribose) polymerase (PARP) inhibitors exploit this deficiency through synthetic lethality and have emerged as promising anticancer therapies, especially in breast cancer gene (BRCA1 or BRCA2) mutation carriers. Apart from inducing synthetic lethality, PARP inhibitors have also been shown to trap PARP1 and PARP2 on DNA, leading to PARP-DNA complexes. This “PARP trapping” potentiates synergism between PARP inhibition and both alkylating agents and platinum-based chemotherapy. However, there are remarkable differences in the ability of PARP inhibitors to trap PARP, based on the size and structure of each separate molecule. Since monotherapy with PARP inhibitors is unlikely to induce cancer cell death in BRCA-proficient tumors, the efficacy of PARP inhibitors could be potentially optimized when combined with DNA-damaging agents, or with molecular targeted agents that also impair mechanisms of DNA repair. Olaparib, rucaparib, and niraparib have all obtained US Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) approval in ovarian cancer in different settings. Veliparib does not yet have an approved label; nevertheless, there are currently promising results available in preclinical and early clinical settings. This comprehensive review summarizes the mechanism of action of veliparib and provides an overview of its early and ongoing clinical investigations.

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Funding

The work was supported by the Medway NHS Foundation Trust, Gillingham, Kent, UK.

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Authors and Affiliations

  1. Medway NHS Foundation Trust, Windmill Road, Gillingham, Kent, ME7 5NY, UK

    Stergios Boussios & Afroditi Karathanasi

  2. AELIA Organization, 9th Km Thessaloniki - Thermi, 57001, Thessaloniki, Greece

    Stergios Boussios

  3. Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 22, 90029, Oulu, Finland

    Peeter Karihtala

  4. Cambridge University Hospitals NHS Foundation Trust, Hills Rd, Cambridge, CB2 0QQ, UK

    Michele Moschetta

  5. Kent Oncology Centre, Maidstone and Tunbridge Wells NHS Trust, Hermitage Lane, Maidstone, Kent, ME16 9QQ, UK

    Charlotte Abson

  6. Leicester Diabetes Research Centre, Gwendolen Road, Leicester, LE5 4PW, UK

    Nikolaos Zakynthinakis-Kyriakou

  7. East and North Hertfordshire NHS Trust, Lister Hospital, Coreys Mill Lane, Stevenage, SG1 4AB, UK

    Jake Edward Ryan

  8. Department of Urology, Medway NHS Foundation Trust, Windmill Road, Gillingham, Kent, ME7 5NY, UK

    Matin Sheriff

  9. Department of Cancer Medicine, Gustave Roussy Institut, 94805, Villejuif, France

    Elie Rassy

  10. Department of Hematology-Oncology, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Beirut, 166830, Lebanon

    Elie Rassy

  11. Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110, Ioannina, Greece

    Nicholas Pavlidis

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Stergios Boussios declares that he has no conflict of interest. Peeter Karihtala declares that he has no conflict of interest. Michele Moschetta declares that he has no conflict of interest. Charlotte Abson declares that she has no conflict of interest. Afroditi Karathanasi declares that she has no conflict of interest. Nikolaos Zakynthinakis-Kyriakou declares that he has no conflict of interest. Jake Edward Ryan declares that he has no conflict of interest. Matin Sheriff declares that he has no conflict of interest. Elie Rassy declares that he has no conflict of interest. Nicholas Pavlidis declares that he has no conflict of interest.

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Boussios, S., Karihtala, P., Moschetta, M. et al. Veliparib in ovarian cancer: a new synthetically lethal therapeutic approach. Invest New Drugs 38, 181–193 (2020). https://doi.org/10.1007/s10637-019-00867-4

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