PARP inhibitors in ovarian cancer

Abstract

Poly-ADP-ribose polymerase inhibitors (PARPis) are the most active and interesting therapies approved for the treatment of epithelial ovarian cancer. They have changed the clinical management of a disease characterized, in almost half of cases, by extreme genetic complexity and alteration of DNA damage repair pathways, particularly homologous recombination (HR) deficiency. In this review, we provide an updated overview of the available results of recent clinical trials on the three Food and Drug Administration and European Medicines Agency approved PARPis in ovarian cancer: olaparib, niraparib, and rucaparib. Furthermore, we anticipate the future perspective of combination regimens with antiangiogenic, immunocheckpoint inhibitors, and other biological agents as strategies to overcome resistance mechanisms, potentiate the therapeutic efficacy, and expand their clinical use in non-HR deficient tumors. Mechanism of action of PARPs and PARPs inhibitors PARPs are a family of 17 nucleoproteins characterized by a common catalytic site that transfers an ADP-ribose group on a specific acceptor protein using NAD + as cofactor. Interestingly, most PARP members are able to transfer only a mono-ADP ribose group to their target proteins, whereas PARP1, PARP2, PARP3, PARP5a, PARP5b characteristically add repeated ADP-ribose units, thus generating long poly(ADP-ribose) (PAR) chains [5]. This post-translational protein modification is named PARylation and allows PARPs involvement in different cellular activities. In this regard, PARP1 is the best characterized PARP. PARP1 modulates chromatine structure via PARylation of core histone proteins resulting in chromatine relaxation, thus enabling replication, repair, and transcription processes [6]. As to transcription, PARP1 plays a pivotal role in its regulation by both serving as a transcriptional cofactor and by hindering methylation of specific sequences, like those of housekeeping genes (Fig. 1a/b). To date, activation of PARP-1, dependent on CCCTC binding factor (CTCF), appears to affect DNA

PARP and PARG inhibitors in cancer treatment

“…Last, in 2018, olaparib and talazoparib were approved for human epidermal growth factor receptor type 2 (HER2)-negative locally advanced or metastatic breast cancer with germline BRCA1/2 mutations. Multiple clinical trials carried out since 2009 have demonstrated PARP inhibitor efficacy in BRCA mutated ovarian and breast cancer, but also prostate, pancreatic cancer, and small cell lung carcinoma (SCLC), irrespective of the BRCA status (Weaver and Yang 2013;Sonnenblick et al 2015;Mirza et al 2018;Franzese et al 2019;Keung et al 2019;Mateo et al 2019;Pant et al 2019;Pilie et al 2019a). Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) joined the stage once structures of the PARG catalytic site became available (Slade et al 2011;Dunstan et al 2012;Kim et al 2012; Barkauskaite et al 2013).…”

Nobiletin induces growth inhibition and apoptosis in human nasopharyngeal carcinoma C666‐1 cells through regulating PARP‐2/SIRT1/AMPK signaling pathway

“…PARPs catalyze a reaction in which the ADP-ribose moiety of NAD + is transferred to a receptor amino acid, building poly(ADP-ribose) (PAR) polymers (Mégnin-Chanet et al, 2010). PARP-1, the founding member of the PARP superfamily, has been demonstrated to regulate the growth of various tumor cells, such as breast cancer, ovarian cancer, and NPC (Chen, Zhao, et al, 2015;Franzese et al, 2019;Nur Husna, Tan, Mohamud, Dyhl-Polk, & Wong, 2018). PARP-2 possesses a catalytic domain structurally similar to PARP-1, whereas it is less active than PARP-1 (Ali et al, 2016).…”

The Application of Biomaterials in the Treatment of Platinum‐Resistant Ovarian Cancer

“…[25] Drugs that have shown efficacy in BRAC1/2 carriersw ith de-ficientH Rr epair ovarian cancers include poly(ADP-ribose) polymerase (PARP) inhibitors such as olaparib, rucaparib,a nd niraparib. [26] Cancer cells use PARP proteins in av ariety of DNA damage repair mechanisms and the inhibition of PARP can trigger death of cancerc ells via synthetic lethality when another mechanism for repairing DNA is defective. PARP inhibitors have traditionally been used in platinum sensitive cancers, but in ar ecent Phase II clinical trial, single agent olaparib treatment showed favorable responses in women with OCpt, including those with BRCA wild-type disease (ClinicalTrials.gov information:N CT02822157).…”