The high mortality (>80%) seen in high-grade serous ovarian cancer (HGSOC) highlights the need for more efficient therapies to be identified. Insights into the pathways involved in the development, progression and treatment response of human cancers can be obtained from genetically engineered mouse models (GEMM). The proliferative/C5 subtype of HGSOC has a particularly poor prognosis and is characterized by genes expressed in mesenchymal development and high expression of transcription factors, such as HMGA2, a downstream target of the LIN28B/MYCN/let7 pathway. We set out to generate a GEMM of C5 HGSOC by driving overexpression of Lin28B or MYCN together with dysregulation of p53 in fallopian tube secretory epithelial cells. Interestingly, using two different GEMM models we obtained ovarian/fallopian tube carcinosarcomas. Ovarian carcinosarcoma (OCS) is a rare cancer, composed of both epithelial (carcinomatous) and mesenchymal (sarcomatous) components, for which few treatment options are available. OCS is thought to be derived from HGSOC as they share a similar genomic profile, including TP53 gene dysfunction (>95%) and HMGA2 overexpression (64% of HGSOC and 60% of OCS).
To investigate the relevance of our GEMM tumours to human carcinosarcomas we analysed RNAseq data from primary and patient-derived xenografts (PDX) of carcinosarcomas and compared to high-grade serous samples. MYCN was highly expressed in the carcinosarcomas, as in our GEMM, and further suggests a close link between C5 HGSOC and OCS. It has been published that C5 HGSOC cell lines are susceptible to anti-microtubule agents, therefore we tested the efficacy of vinorelbine and eribulin for the treatment of OCS using our GEMM and PDX models. While most tumours respond well initially, many relapse. To achieve complete and sustained responses in HGSOC and OCS we are currently investigating combination treatments in our PDX models, including the combination of anti-microtubule agents or PARP inhibitor, depending on the genotype of the tumour, with immunotherapy (pembrolizumab) in human immune system (HIS) mice.