ReviewPARP inhibitors: A new era of targeted 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 Army—W81XWH-14-1-0092, the David Mazzone Awards program of Prostate Cancer Research Foundations, and NSF-DGE—0965843.
Provenance and peer review
Commissioned; externally peer reviewed.
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