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

• DOI: 10.1186/s12967-020-02613-4
• Publication Date: 2020-11-19T22:45:47Z
• Authors: Razan Sheta; Magdalena Bachvarova; Marie Plante; Marie-Claude Renaud; Alexandra Sebasti...; Jean Gregoire; Jamilet Miranda N...; Ricardo Bringas P...; Jean-Yves Masson; Dimcho Bachvarov
• Keywords: Serous ovarian cancer; Olaparib; Identification

Poly(ADP-ribose) polymerase inhibitors (PARPis) specifically target homologous recombination deficiency (HRD) cells and display good therapeutic effect in women with advanced-stage BRCA1/2-mutated breast epithelial ovarian cancer (EOC). However, about 50% of high grade serous cancers (HGSOC) present HRD due to epigenetic BRCA1 inactivation, as well genetic/epigenetic inactivation(s) other HR genes, a feature known "BRCAness". Therefore, there is potential for extending the use PARPis these patients if status can be identified.We have developed 3D (spheroid) functional assay assess sensitivity two (niraparib olaparib) ascites-derived primary cell cultures (AsPCs) from HGSOC patients. A method AsPCs preparation was established based on matrix (agarose), allowing easy isolation successive propagation monolayer AsPCs. Based this method, we performed cytotoxicity assays 42 grown both monolayers spheroids.The response treatment AsPCs, significantly higher, compared 88% 52% displayed niraparib olaparib respectively, while 66% were sensitive 38% olaparib, latter being more consistent previous estimates (40%-60%) EOC. Moreover, stronger cytotoxic which confirmed by consecutive analyses pathway activity (γH2AX foci formation) PARPis-sensitive resistant Global gene expression comparison 6 PARPi-resistant PARPi-sensitive indicative predominant downregulation numerous genes networks previously demonstrated roles EOC chemoresistance, suggesting that could enhanced chemotherapeutic drugs, commonly applied management. Microarray data validation identified 24 biomarkers associated sensitivity. The differential 7 selected consecutively immunohistochemistry matched tumor samples.The application possible predictive significance therapy now need testing setting clinical trial.