Parp Inhibitors for the Treatment of Ovarian Cancer

Abstract

The standard of treatment for advanced ovarian cancer is represented by optimal surgical debulking preceded or followed by chemotherapeutic regimens including taxanes and platinum agents, possibly associated with bevacizumab and/or intraperitoneal therapy. Despite this comprehensive treatment strategy, almost 75% of patients relapse or progress and are therefore candidates for a second-line treatment, showing, at this point, less chemo-sensitivity and worse prognosis. An interesting approach to improve outcomes of these patients has been developed in the last decade, in BRCA-related ovarian cancer. Mutations in one of the BRCA genes result in impaired homologousrecombination DNA repair, which causes genetic abnormalities that promote carcinogenesis. Interestingly, this defect has been exploited by the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors to provide specific cancer cell cytotoxicity. Particularly, the inhibition of PARP in BRCAmutation carriers leads to the persistence of DNA damage usually repaired by the homologousrecombination system, resulting in cell cycle arrest and thus apoptosis. Despite the mechanism of action, an activity of PARP inhibitors was also observed in "BRCAness" ovarian tumors, and in BRCA-related tumors other than ovarian, suggesting that these agents may be active regardless of BRCA mutation status or site of origin. This review aims to describe the principal evidence that led to the development and the study of PARP inhibitors and to discuss their main implications in our daily clinical practice.

Exploiting DNA repair defects in colorectal cancer

“…Poly-(ADP) ribose polymerase inhibitors (PARPi) have been used as anticancer agents since the early 2000s (McCabe et al, 2006), and the first PARPi, olaparib, was approved for BRCA-mutated ovarian cancer in 2014 (Kim et al, 2015). Approval of these drugs was first given for the treatment of breast and ovarian cancers, and studies found that this therapy regimen was most effective in cells that carry functional defects in DNA DSB pathways, most notably in BRCA-mutated cells (Cortesi et al, 2018;Ghiringhelli et al, 2016;Lin et al, 2014;Lord and Ashworth, 2017;Mittica et al, 2018;Sunada et al, 2018). Recent studies ascribed this synthetic lethality phenotype to the loss of PARP activity at replication forks, suggesting that PARP inhibition promotes rapid fork progression, leading to increased genome instability that the cell cannot overcome when HR defects are also present (Maya-Mendoza et al, 2018).…”

MUS81 Inhibition Increases the Sensitivity to Therapy Effect in Epithelial Ovarian Cancer via Regulating CyclinB Pathway

“…PARP inhibitors such as Olaparib are currently a novel targeted drugs for the treatment of BRCA-mutant ovarian cancer. The use of an HR repair defect mechanism leads to cell cycle arrest and apoptosis 30. Inhibition via gene targeting inhibition in BRCA-proficient tumors in combination with Olaparib could result in a synergistic increase in DNA damage and G2/M cell-cycle checkpoint defects, which may allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe 31.…”

Germline Mutations in Other Homologous Recombination Repair-Related Genes Than BRCA1/2: Predictive or Prognostic Factors?

“…Besides, another two PARP inhibitors, niraparib [ 16 ], and rucaparib [ 17 ] have been granted approval in the maintenance setting of ovarian cancer, regardless of BRCA1/2 status. Furthermore, both olaparib [ 18 ] and talazoparib [ 19 ] are approved in human epidermal growth factor receptor 2 (HER2)-negative, g BRCA1/2 -mutation-associated metastatic breast cancer [ 20 ]. Finally, several trials of olaparib in patients with g BRCA1/2 mutations identified responders beyond ovarian or breast cancer patients, suggesting that other HRR-defective tumors could be suitable for PARPi treatment [ 14 ].…”