Ovarian carcinosarcoma genomics and pre-clinical models highlight the N-MYC pathway as a key driver and susceptibility to EMT-targeting therapy

• Published in: bioRxiv
• Main Authors: Gwo, Yaw Ho, Kyran, Elizabeth L, Bedo, Justin, Wakefield, Matthew J, Ennis, Darren P, Mirza, Hasan B, Lieschke, Elizabeth, Vandenberg, Cassandra J, Kondrashova, Olga, Upstill-Goddard, Rosie, Bailey, Ulla-Maja, Dowson, Suzanne, Roxburgh, Patricia, Glasspool, Rosalind M, Bryson, Gareth, Biankin, Andrew V, Cooke, Susanna L, Ratnayake, Gayanie, Mcnally, Orla, Traficante, Nadia, Australian Ovarian Cancer Study, Defazio, Anna, Weroha, John, Bowtell, David D, Mcneish, Iain A, Papenfuss, Anthony T, Scott, Clare L, Barker, Holly E
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 24.11.2020
• Subjects: Chemotherapy; Cholesterol; DNA sequencing; Drug delivery; Genomics; Immune response; Immunosuppressive agents; Immunotherapy; Mesenchyme; Myc protein; Oncology; Ovarian carcinoma; Ovaries; Platinum; Sarcoma; Tumors; Vinorelbine
• DOI: 10.1101/2020.11.24.396796

Abstract Ovarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options. OCS is hypothesised to develop via the combination theory from a single progenitor, resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). We show OCS from 18 women to be monoclonal through analysis of DNA variants from isolated carcinoma and sarcoma components. RNA sequencing indicated the carcinoma components were more mesenchymal when compared with pure ovarian carcinomas, supporting the conversion theory. We used pre-clinical OCS models to test the efficacy of microtubule-targeting drugs, including eribulin, which has been shown to reverse EMT characteristics. We demonstrated that microtubule inhibitors, vinorelbine and eribulin, were more effective than standard-of-care platinum-based chemotherapy. Eribulin reduced mesenchymal characteristics, N-MYC expression and cholesterol biosynthesis. Finally, eribulin induced a strong immune response, supporting immunotherapy combinations in the clinic. Competing Interest Statement Eisai Inc provided drug support for this study. Rosalind M. Glasspool declares Advisory boards for Clovis, Tesaro and AstraZeneca. Andrew V. Biankin declares Personal and Financial interest in BMS, AstraZeneca, MyTomorrows, Elstar Therapuetics, IP Financial Interest in Agilent Technologies, Leadership role, stock ownership in Cumulus Oncology, Nodus Oncology, ConcR, Cambridge Cancer Genomics. Iain A. McNeish declares Advisory Boards for Clovis Oncology, Tesaro/GSK, AstraZeneca, Roche, Scancell, Carrick Therapeutics, Takeda Oncology; Institutional grant support from AstraZeneca. David D Bowtell declares Consultant for Exo Therapeutics. Research Support for AstraZeneca, Roche, GNE, Beigene. Clare L. Scott declares Advisory Boards for AstraZeneca, Clovis Oncology, Roche, Eisai Inc, Sierra Oncology, Takeda, MSD and Grant/Research support from Clovis Oncology, Eisai Inc, Sierra Oncology, Roche and Beigene. Other authors declare no conflicts of interest.