PARP Inhibitors for Breast and Ovarian Cancers

John F. Hilton, MD
Published: Wednesday, Nov 26, 2014

Abstract

PARP inhibitors represent an exciting new class of anticancer agents and are currently being evaluating in phase III for a number of different indications. Clinically, PARP inhibitors demonstrate activity in tumors which lack a functional homologous recombination (HR) system and are being developed primarily for patients with germline BRCA1 or BRCA2 mutations and high-grade serous ovarian cancer. This review will discuss the clinical experience with PARP inhibitors so far and the current registration strategies being undertaken. In addition, the review will discuss the rationale behind the recent work combining PARP inhibitors with other targeted agents.
 

Introduction

DNA strand Poly (ADP-ribose) polymerase (PARP) inhibitors are pharmacologic agents that inhibit the PARP enzymes within the cell. This class of agents represents an exciting potential therapy in patients with defects in the HR repair pathway. In particular, PARP inhibitors are being developed for patients with germline BRCA1 or BRCA2 mutations, although the spectrum of tumors that may be treated effectively by these agents may be larger than this specific population. This article will review: 1) the role of PARP within the cell and why its inhibition is effective in BRCA-deficient tumors; 2) an overview of key clinical trials which have been completed for PARP inhibitors and how they have guided clinical development of these agents; 3) the clinical potential for PARP inhibitors in combination with other targeted agents.

The Role of PARP and Rationale for Its Inhibition in BRCA-Deficient Tumors

In all human cells, DNA is subjected to frequent damage secondary to environmental insults, toxic metabolites, and DNA replication errors. Single-stranded breaks (SSBs), defined as a loss on continuity in the deoxyribose sugar backbone in one strand of the DNA double helix with the possible loss of the nucleotide base at the site of the break,1 are one of the most frequent mechanisms of damage.2 Detection of SSBs and repair of SSB is thought to require the activity of PARP enzymes as cells that have lost PARP enzymatic activity accumulate SSBs in their DNA. As a consequence of failing to repair SSBs, double-stranded breaks (DSBs) in DNA occur as replication forks encountering SSBs either stall or collapse.3-5 Fatal if not repaired, 2 major DSB repair pathways have evolved: 1) HR, a largely error-free mechanism to repair DSBs; and, 2) non-homologous end-joining (NHEJ), which randomly attaches DSB together, leading to potentially significant new insertions, deletions, base-substitutions or translocations to a cell’s genome.6

The initiation and completion of HR repair is highly dependent on intact BRCA1 and BRCA2 function; therefore, PARP inhibition can potentially lead to tumor cell death in BRCA1/2-deficient tumors. The exact mechanism by which PARP induces cell death in BRCA1/2-deficient tumors is uncertain with 4 mechanisms proposed. First, by failing to repair the DSB through HR, cellular apoptotic pathways are activated leading to cell death. Second, PARP inhibition increases the activity of the NHEJ repair pathway in HR-deficient cells through phosphorylation of DNA-dependent protein kinase substrates, leading to accumulation of genetic errors in essential cellular genes and eventual cellular death secondary to genomic instability.7 Third, it has been proposed that PARP inhibitors work by preventing the release of PARP/BER complex located at a SSB. This “PARP-trapped” BER-repair complex physically prevents progression of replication forks and is thought to require HR-dependent repair in order to remove from DNA.8,9 Finally, it has been proposed that stalled replication forks can be repaired by either DSB-repair HR or a PARP-dependent HR-repair mechanism, with PARP inhibitors preventing PARP-dependent HR repair.10 In cells which are HR-deficient, inhibition of the PARP activity prevents PARP-mediated HR repair of stalled replication forks, resulting in replication failure and synthetic lethality.11 Helleday’s review on this topic is recommended for any reader interested in further details regarding the mechanism of PARP inhibitors in cancer cells.11

Figure. Presumed Mechanism for Synthetic Lethality Using PARP Inhibitors in BRCA-Deficient Tumors

Presumed Mechanism for Synthetic Lethality Using PARP Inhibitors
in BRCA-Deficient Tumors

HR, homologous recombination.
Shapiro GI.  Biologic Principles of Targeted Combination Therapy: PARP-1 and Checkpoint Kinase 1 and augmentation of the DNA damage response.  Educational Session, Tumor Biology, American Society of Clinical Oncology, 2012, Chicago, IL. Used with permission




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