Ovarian carcinosarcoma (OCS) represents just 1-4% of all ovarian cancer cases. Despite a similar molecular profile to high grade serous ovarian cancer (HGSOC), OCS tumours do not respond to therapies that are efficacious in HGSOC, and OCS will typically recur within 12 months with the average overall survival for OCS patients less than 2 years.
The biphasic nature of ovarian carcinosarcoma is believed to underlie its poor prognosis. Comprised of both a carcinoma and sarcoma, many postulate that it is a conversion of the carcinoma into the sarcoma via epithelial-to-mesenchymal transition (EMT) that leads to its development. Our lab recently performed a drug screen testing 3800 compounds on a cell line derived from our original OCS genetically-engineered mouse model developed within the WEHI-Stafford Fox Rare Cancer Program based at the Walter and Eliza Hall Institute of Medical Research (WEHI-SFRCP). This screen identified several EMT targeting agents as being efficacious in killing OCS cells. Ten compounds were selected for further validation. These compounds were tested in 2D drug assays on three OCS cell lines derived from patient-derived xenografts (PDX) generated within WEHI-SFRCP and two well-known HGSOC cell lines (OVCAR8 and PEO4). The compounds were also assessed on a suite of 3D organoid models derived from five OCS PDX models and two HGSOC PDX models.
Drug sensitivity, as measured by end-point analysis via Cell Titre Glo, was most consistently observed for the proteosome inhibitors Bortezomib and MG-132, followed by the FGFR inhibitor PD-166285. The HSP90 inhibitor BIIB021 also induces cell death at a nanomolar range but this result is not as reproducible, particularly across the 3D assays. The future directions of this project are to further validate the compounds showing the greatest efficacy in the 2D and 3D assays, in our collection of 10 OCS PDX models, and relate these to the molecular characteristics of the individual cases and patient outcomes/response to therapy. It is the aim of this project to provide preclinical evidence for drugs that target a unique feature of OCS - the EMT which contributes to the sarcomatous component – to either kill the tumour cells themselves, or at least increase the responsiveness of OCS to more standard therapies.