Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPIs) - targeted therapy

ABSTRACT: Epithelial ovarian cancer (EOC) is the most serious of all gynecological cancers, mainly due to its asymptomatic nature and the resulting lack of early diagnosis. Cells with defects in DNA repair accumulate genetic abnormalities and may progress to become malignant. However, this DNA repair deficiency makes tumor cells vulnerable to further compromise by therapeutic targeting of other associated pathways, using agents such as poly-ADP ribose polymerase (PARP) inhibitors (PARPIs). A major challenge facing the use of PARPIs is the paucity of functional assays/biomarkers to identify HGSOC patients who may benefit from these agents, in particular the subgroup with non-BRCA-mutant, HR-deficient cancers. Our study presents a predictive tool which may help identify sporadic HGSOC patients, most likely to respond to PARPIs therapy. We have successfully developed and employed a functional 3D assay to test PARPIs sensitivity in EOC based on ascites-derived primary cell cultures (AsPCs) from EOC patients. Our data showed that this approach can better mimic primary tumor response to PARPIs treatments. We have successfully grown 42 AsPCs, and have prepared spheroid cultures from AsPCs using 3D-Biomatrix technology. We were able to monitor the cytotoxic effect on AsPCs spheroids of each of the drugs olaparib (Astra- Zeneca) and niraparib (Tesaro, licensed from Merck). Our results showed that AsPCs appear to be much more sensitive to niraparib compared to olaparaib. The cytotoxic effect observed by the two drugs was confirmed by analysis of γH2AX foci formation. Data demonstrated γH2AX foci to significantly increase in cell lines that are sensitive to the drug treatments. Consecutively, epithelial-to-mesenchymal transition (EMT) was also assessed in resistant vs. sensitive cell lines. Our results indicate that PARP inhibition can inhibit the acquisition of an EMT phenotype in sensitive cell lines, but not in resistant cell lines. Moreover, global gene and microRNA expression profiling of PARPI-R and PARPI-S spheroid cultures identifies gene/mRNA biomarkers, associated with PARPI sensitivity. We believe our predictive tool has helped classify genes that can be clinically relevant in identifying PARP inhibitor sensitivity in ovarian cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149940 | GEO | 2020/11/20

REPOSITORIES: GEO