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REVIEW ARTICLE
A Review of PARP Inhibitors in Clinical Development Sarah A. Hopps, PharmD; Carla D. Kurkjian, MD; Shubham Pant, MD
J Hematol Oncol Pharm. 2012;2(1):18-28. www.JHOPonline.com Disclosures are at end of text
Background: The development of poly(ADP-ribose) polymerase (PARP) inhibitors has expanded the potential for targeting DNA damage in cancer cells. The efficacy of PARP inhibitors in cancer therapy is being investigated in a number of clinical trials in a variety of tumor types, including and beyond the expected BRCA mutation malignancies. Objective: To review the evidence from ongoing clinical trials regarding PARP inhibitors currently in development and to describe the growing role of PARP inhibition in biomarker development and in personalized medicine. Discussion: PARP inhibitors possess a unique mechanism of action, targeting cancer cells that have deficient DNA damage repair mechanisms. Preclinical studies have shown that PARP inhibitors are especially cytotoxic in cells with BRCA mutations compared with the wild-type cells. Clinical trials are investigating new PARP inhibitors for the treatment of a variety of tumors, with maximal efficacy demonstrated in patients with mutations in the BRCA genes. This review outlines the mechanism of action of PARP inhibitors that are furthest in clinical development and the available evidence from these clinical trials. There are currently at least 9 PARP inhibitors in development; of these, the PARP-1 and PARP-2 inhibitors olaparib, veliparib, and iniparib are furthest along, with all 3 showing promising results. Conclusion: The benefits of the PARP inhibitors will have to be weighed against their toxicities in the long-term. The strength of these novel agents lies in targeting the weakness of tumors, and that improves clinical outcomes. The results of ongoing clinical trials will help to determine whether these medications will be effective in a wide range of tumors or only in the subset of BRCA mutation carriers.
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he development of poly(ADP-ribose) polymerase (PARP) inhibitors has expanded the potential for targeting DNA damage in cancer cells. The efficacy of PARP inhibitors in cancer therapy is the subject of an increasing number of clinical trials in a variety of tumor types, including and beyond the expected BRCA mutation malignancies. The established mechanism of action of PARP inhibitors is an important addition to the field of rationally designed drug development through novel trial design, as well as to the development of biomarker investigation. There are currently at least 9 PARP inhibitors in clinical development (Table 1). In this review article we describe the evolving role of PARP inhibition in the landscape of personalized therapy, focusing on the 3 PARP inhibitors that are furthest in clinical development.
Dr Hopps is Clinical Specialist, Hematology/Oncology, Rush University Medical Center; Dr Kurkjian is Assistant Professor of Medicine; and Dr Pant is Assistant Professor of Medicine, Peggy and Charles Stephenson Cancer Center at the University of Oklahoma Health Sciences Center, Oklahoma City.
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The Rationale for PARP Inhibition The accumulation of DNA damage is central to carcinogenesis.1 The mechanisms for repairing singlestrand DNA breaks include the base excision repair pathway, in which the PARP family plays a key role.2,3 The most abundant of this group of enzymes is PARP1; its inhibition leads to double-strand breaks at the replication forks, in the absence of homologous repair.4 The PARP enzymes function through the transfer of ADP-ribose moieties from intracellular nicotinamide adenine dinucleotide, which leads to the creation of ADP-ribose polymers on the PARP protein and surrounding histones.5 It is believed that these negatively charged ADP-ribose polymers then attract DNA repair proteins, such as XRCC1.6 The products of the tumor-suppressor genes BRCA1 and BRCA2 are integral to homology-directed repair, and a deficiency in these genes leads to disordered DNA damage repair and subsequent carcinogenesis.7-9 Based on the premise that in BRCA mutation cells the base excision repair pathway becomes essential to viability,
www.JHOPonline.com
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Vol 2, No 1