Elsevier

Maturitas

Volume 81, Issue 1, May 2015, Pages 5-9
Maturitas

Review
PARP inhibitors: A new era of targeted therapy

https://doi.org/10.1016/j.maturitas.2015.01.015Get rights and content

Highlights

  • PARP inhibitor (Lynparza™) recently approved for BRCA deficient Ovarian cancer treatment.

  • PARP inhibitor therapy extends beyond BRCA deficient cancers.

  • New synthetic lethality pathways for PARP inhibition therapy are being studied extensively.

  • Clinical trials in combination with chemo-and radiation therapies are currently being conducted.

Abstract

Personalized medicine seeks to utilize targeted therapies with increased selectivity and efficacy in preselected patient cohorts. One such molecularly targeted therapy is enabled by inhibiting the enzyme poly(ADP-ribose) polymerase (PARP) by small molecule inhibitors in tumors which have a defect in the homologous DNA recombination pathway, most characteristically due to BRCA mutations. Olaparib, a highly potent PARP inhibitor, has recently been the approved for ovarian cancer therapy by the FDA and European commission in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with BRCA1 or BRCA2 mutations. Currently, clinical trials with several PARP inhibitors are being conducted to assess the toxicities, the efficacies and the benefit of the drugs as monotherapies or combined with radiation or other chemotherapeutic agents, in ovarian, breast, prostate, rectal, lung, pancreatic, peritoneal, head and neck, brain, squamous cell carcinomas and sarcomas, to list a few. In this review, our focus is to outline the emerging molecular mechanisms, preclinical evidence and clinical applications of PARP inhibitors especially in nonBRCA cancers, and review the combination strategies compatible with PARP inhibitor therapy.

Section snippets

Mechanism of action

DNA damage in cells manifests mainly as single-strand breaks (SSB's), double strand breaks (DSB's) or replication fork stalling. In these instances the PARP-1 enzymes are recruited to regulate the process of autoPARylation. The PAR polymers thus synthesized rapidly bind to DNA strand breaks to reseal or repair the damage. Because of the high negative charge of PAR polymers, they eventually dissociate from the DNA–PARP repair complexes at the site signifying the completion of the repair process.

Expanding the PARP inhibitor applicability

PARP inhibitor therapy made its way into clinical trials after the discovery of the synthetic lethality of PARP inhibition in the presence of BRCA 1/2 mutations, which led to selective cell death, particularly in ovarian and breast cancers. Preliminary clinical evidence with BRCA mutant patients showed significant clinical efficacy upon chronic treatment with olaparib [5], [7]. Recent studies have also indicated the pivotal role of BRCA1, BRCA2 dysfunctional pathology in prostate cancers in

Interplay of PARP inhibitors with signaling pathways

In addition to the DNA damage repair functions, PARP-1 also regulates both tumor growth and progression through transcriptional regulatory functions. The transcriptional involvement of PARP-1 in androgen regulation has been observed to suppress critical signaling pathways, specifically for prostate cancer cell survival and progression. PARP-1 thus appears to be involved in the Androgen Receptor (AR) sensitive cancers where it is enzymatically linked to AR activity and progression of cancer [6].

Combination therapy with chemotherapeutics and radiation

A number of preclinical studies have demonstrated that PARP inhibitors can be potentially viable as chemopotentiators or chemo- and radiation sensitizers. These studies have led to clinical trials of PARP inhibitors in combination with chemotherapeutics that lead to DNA damage (Table 1), with the PARP inhibitor blocking the subsequent DNA repair mechanisms selectively in cancer cells. Some of the drugs being used with PARP inhibitors include platinum based DNA damaging agents such as cisplatin,

Resistance to PARP inhibitors

Three mechanisms of resistance to PARPi therapy have been identified thus far: (1) Upregulation of PgP transporter, (2) loss of PARP1 expression, (3) restoration of the HR pathway in BRCA targeted tumors [17], [28]. Upregulation of PgP pumps is a common pharmacological effect that reduces the efficacy of a number of drugs including PARP inhibitors by effluxing the drugs out of the cell and thus reducing the intracellular concentration of the drug available for the therapy. Since PARP inhibitors

Challenges of PARP inhibitor therapies

The predominant challenge with PARPi therapy is the suboptimal availability and accumulation of the drug at the intended anatomical tumor site owing to the pharmacokinetic properties of the poorly water soluble oral inhibitors. Another challenge especially with the combination therapies, are the concomitant and induced toxicities and pharmacological drug-drug interactions. Hence, the optimization of dosage regimen becomes a key factor for a successful clinical trial with the combination

Contributors

Shifalika Tangutoori: Concept proposal, outline of the paper, literature study, writing, editing, table preparation.

Paige Baldwin: Contributed to sections on PARP resistance, mechanism of action, reviewed the tables and the paper in general.

Sridhar Srinivas: Initiated the review, approved the concept, writing, coordination, editing, reviewing tables and the manuscript.

Competing interests

No potential conflict of interest to disclose.

Funding

This work was supported by Ovarian Cancer Research Program ArmyW81XWH-14-1-0092, the David Mazzone Awards program of Prostate Cancer Research Foundations, and NSF-DGE0965843.

Provenance and peer review

Commissioned; externally peer reviewed.

References (29)

  • R. Scully

    Role of BRCA gene dysfunction in breast and ovarian cancer predisposition

    Breast Cancer Res: BCR

    (2000)
  • S. Fan et al.

    BRCA1 as a potential human prostate tumor suppressor: modulation of proliferation, damage responses and expression of cell regulatory proteins

    Oncogene

    (1998)
  • E.M. Rosen et al.

    BRCA1 and prostate cancer

    Cancer Invest

    (2001)
  • A. Sonnenblick et al.

    An update on PARP inhibitors—moving to the adjuvant setting

    Nat Rev Clin Oncol

    (2015)
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