Identification of Functional Targets in Epithelial Ovarian Carcinoma

Abstract

Epithelial ovarian cancer (EOC) remains the most lethal gynaecologic malignancy. Possible reasons for the low survival of EOC are high incidence of chemoresistance and that high degree of heterogeneity is not considered in the current standard of care. To address the heterogeneity, EOC was previously proposed to be classified into five molecular subtypes (Epi-A, Epi-B, Mes, Stem-A, Stem-B). Thus, in the first part of the thesis, a pooled shRNA lentivirus library was used to screen for subtype-specific molecular targets. Two genes involved in tubulin processing, TUBGCP4 and NAT10, were found to be essential for the poor-prognosis Stem-A subtype, and linked the subtype with tubulin polymerisation inhibitory drugs. In the second part, shRNA lentivirus library was again used to screen for cisplatin resistance relevant genes, and six genes, including RPS6KA1 were identified. Treatment with SL0101, a RPS6KA1-specific inhibitor, was found to increase the cisplatin sensitivity of Epi-A cell lines, but not Stem-A cells. Hopefully, these findings can contribute to the improvement of therapeutic regimens for EOC patients.