Abstract 1700: Dasatinib and everolimus show synergistic growth inhibition with paclitaxel in an ovarian granulosa cell tumor model

Adult-type granulosa cell tumor (AGCT) is a rare form of ovarian cancer characterized by a somatic mutation in FOXL2 (402C>G). Although AGCT is known for its indolent growth, up to 30% of AGCTs recur, and with recurrence the mortality reaches 60-70%. For recurrent tumors, surgery is often infeasible and the current chemotherapy regimen have only modest effect. Therefore, new treatment strategies are needed.We performed high-throughput drug sensitivity and resistance testing (DSRT) utilizing six patient-derived primary cell cultures (2 primary and 4 recurrent AGCTs), and a human AGCT cell line (KGN). AGCT cells were exposed to 232 investigational compounds and approved chemotherapeutics. Selective efficacy was assessed against healthy bone marrow cells and the most potent compounds were further tested in a combination matrix with paclitaxel in KGN cells. The expression levels of the drug targets were verified by RNA-sequencing, and immunohistochemistry in a tissue microarray of 90 AGCT samples.The response profiles of the AGCTs and the AGCT cell line were similar, with no significant variation between the primary and recurrent tumors. Inhibitors of survivin, HSP90, mTOR, and SRC exhibited the highest selective efficacies, whereas taxanes were the most potent traditional chemotherapeutics. The combination of SRC-inhibitor dasatinib and paclitaxel showed unanticipated synergistic growth inhibition already at low doses, with a 50% increase in sensitivity compared to the effects o...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Experimental and Molecular Therapeutics Source Type: research