Abstract and Introduction
Ovarian cancer is the most lethal gynecologic malignancy. The long-established primary treatment for ovarian cancer consisted of surgical cytoreduction followed by platinum-based chemotherapy. Unfortunately, this therapeutic approach is related to a high frequency of early relapses. Further chemotherapy is necessary for recurrent disease, but very few patients can be cured. Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in various DNA repair activities. PARP inhibition leads to synthetic lethality in BRCA mutated or homologous recombination deficient tumors. The development of PARP inhibitors has changed the way ovarian cancer patients are treated. Olaparib, niraparib and rucaparib are orally active and have demonstrated efficacy for both maintenance and treatment settings. These three drugs have gained regulatory approval for different clinical circumstances. They have an acceptable toxicity profile and are generally well tolerated. Common class toxicities include hematologic effects, gastrointestinal effects and fatigue. Moreover, new treatment strategies that combine PARP inhibitors with other drugs, such as angiogenic agents, are being explored. The purpose of this review is to describe the evidence that define the current clinical role of PARP inhibitors in ovarian cancer. The implementation of rationally designed new clinical trials will be crucial to facilitate the best selection of patients and to continue improving clinical outcomes.
Eukaryotic cells have evolutionarily developed various mechanisms that ensure the integrity of their genome in order to survive. These processes are known as DNA damage response mechanisms. Physical, chemical and biological agents can weaken the integrity of the DNA, generating ruptures of one (single-strand breaks, SSB) or both (double-strand breaks, DSB) chains. The main mechanisms for SSB repair are repair by base excision (BER) and DNA mismatch (MMR) repair. When the lesions are more extensive and manage to generate DSB, homologous recombination (HR) repair route, which has a high degree of fidelity in error repair, is used. There are other ways of salvage DSB reparation, such as the non-homologous end joining (NHEJ), however, its level of repair fidelity is low and produces errors that in the end can result in a significant commitment in genomic stability and therefore in cell survival.
The canonical mechanisms of DNA damage repair (BER and HR) depend on the formation of macromolecular complexes that group various effector proteins that ensure the correct execution of the damage repair. Among these are the BRCA1 and BRCA2 proteins, which are associated with proteins such as RAD50, RAD51, NBS1, MRE11, ATM, ATR and CHK2.
For recent years, interest in Poly (ADP-ribose) polymerase (PARP) proteins has been focused due to their key participation in the repair processes of both SSB and DSB. PARP enzymes come from a family of 17 members that include PARP1, PARP2, PARP3, PARP5a and PARP5b. PARP1 is the most studied enzyme in the family, given its particular PARylation function, which is a post-translational modification consisting of the addition of ribose poly-ADP to nuclear proteins. PARP detects DNA damage and aids to choice of repair pathway. As explained above, in the context of a deficiency in the canonical repair pathways (e.g., failure of the BRCA function), alternative repair pathways are activated. At this point, the activity of the PARP becomes more important for the organism.
A mutation in the BRCA gene that limits its function compromises the functionality of HR repair. As NHEJ repair is activated, function of PARP1 becomes critical. Without this enzyme, the repair process is highly affected, causing the accumulation of genetic errors, which results in a functional incompatibility of the cell and initiating the process of programmed cell death.
Over 15% of patients with high-grade serous ovarian cancer carry a germline mutation in BRCA1 or BRCA2. PARP inhibitors are synthetic lethal in the presence of BRCA dysfunction and DNA damage. Two articles of preclinical models showed that BRCA mutant cells are highly sensitive to PARP inhibitors.[7,8] These agents have been studied in different ovarian cancer populations that include germline BRCA-mutated, somatic BRCA-mutated, HR deficient and BRCA wild-type patients.
Chin Clin Oncol. 2020;9(4):51 © 2020 AME Publishing Company