Dasatinib And Everolimus Show Synergistic Growth Inhibition With Paclitaxel In An Ovarian Granulosa Cell Tumor Model

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAAdult-type granulosa cell tumor (AGCT) is a rare form of ovarian cancer characterized by a somatic mutation in FOXL2 (402Cu003eG). 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 of either compound alone in AGCT cell line. Similarly, mTOR-inhibitors everolimus, PF-04691502, and AZD8055 showed synergy when combined with paclitaxel. Primary targets of these compounds were expressed at both mRNA and protein level, showing an overall similarity across the tested tumors.This was the first time the DSRT platform was performed on cultures obtained from a solid cancer, providing an intriguing ex vivo tool to identify potential compounds for further clinical testing. The similarity of the drug sensitivity and gene expression profiles across the tumors underline the homogenous nature of AGCT, and suggest the results may be generalized for other AGCTs. Given the suboptimal clinical usability of the current survivin and HSP90 inhibitors, further drug development is needed prior to clinical testing. However, based on the significant synergy found in the present study, clinical trials combining paclitaxel with the readily approved anticancer drugs dasatinib and everolimus are warranted for patients with advanced AGCT.Citation Format: Ulla-Maija Haltia, Noora Andersson, Bhagwan Yadav, Evgeny Kulesskiy, Anniina Farkkila, Annika Riska, Leila Unkila-Kallio, Krister Wennerberg, Tero Aittokallio, Mikko Anttonen. Dasatinib and everolimus show synergistic growth inhibition with paclitaxel in an ovarian granulosa cell tumor model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1700. doi:10.1158/1538-7445.AM2015-1700