Dataset Information

PARP inhibitors in platinum-sensitive high-grade serous ovarian cancer.

ABSTRACT: PURPOSE:Poly(ADP-ribose) polymerase inhibitors (PARPi) have changed the management of high-grade serous ovarian cancer (HGSOC). The rationale for the development of PARPi was based on the concept of synthetic lethality, in which a cell can survive a deficiency of one gene/gene product, but may die if there is a deficiency in a combination of genes/gene products. In women with BRCA1/2 deficiency within their ovarian cancer tissue, inhibition of PARP imposes an intolerable burden of DNA damage repair deficiency and may induce cell death. METHODS:Clinical trials have evaluated PARPi as single-agent therapeutics and as maintenance treatment following platinum-based chemotherapy for HGSOC. Clinical data suggest the most impressive anti-tumour activity occurs in women with platinum-sensitive ovarian cancer and germline or somatic BRCA1/2 mutations (g/sBRCAmt). RESULTS:In the maintenance setting, randomised trials have shown that PARPi compared to placebo reduce the hazard ratio for the development of progressive disease to 0.2-0.27 for patients with a g/sBRCAmt; to 0.34-0.38 for patients with putative evidence of DNA damage repair deficiency; and to 0.35-0.45 in an unselected population with HGSOC. Furthermore, phase 1/2 trials have reported single-agent anti-tumour response rates in gBRCAmt of approximately 50% in platinum-sensitive and 25% in platinum-resistant disease. CONCLUSION:Here, we discuss the evidence for the use of PARPi as single-agent therapeutics and maintenance treatment in HGSOC and evaluate the genetic assays used in clinical trials so far. We discuss the emerging role of platinum sensitivity as a broad eligibility criteria for the use of PARPi.

SUBMITTER: Morgan RD

PROVIDER: S-EPMC5854713 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PARP inhibitors in platinum-sensitive high-grade serous ovarian cancer.

Morgan Robert D RD Clamp Andrew R AR Evans D Gareth R DGR Edmondson Richard J RJ Jayson Gordon C GC

Cancer chemotherapy and pharmacology 20180220 4

<h4>Purpose</h4>Poly(ADP-ribose) polymerase inhibitors (PARPi) have changed the management of high-grade serous ovarian cancer (HGSOC). The rationale for the development of PARPi was based on the concept of synthetic lethality, in which a cell can survive a deficiency of one gene/gene product, but may die if there is a deficiency in a combination of genes/gene products. In women with BRCA1/2 deficiency within their ovarian cancer tissue, inhibition of PARP imposes an intolerable burden of DNA da ...[more]

PMID: 29464354

Similar Datasets

Project description:BackgroundHigh-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum-based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with ineffectiveness of the current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSCs.Experimental designWe tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSC cell lines and patient-derived tumor cells in vitro and in vivo.ResultsWe show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts.ConclusionOur findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic.

Dataset Information

PARP inhibitors in platinum-sensitive high-grade serous ovarian cancer.

Publications

PARP inhibitors in platinum-sensitive high-grade serous ovarian cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets