Virtual Live Oral Presentation 34th Lorne Cancer Conference 2022

Ovarian carcinosarcoma genomics and preclinical models enable identification novel mechanisms of action of eribulin on N-MYC and the mevalonate pathway (#3)

Holly Barker 1 2 , Gwo Yaw Ho 3 , Elizabeth Kyran 1 2 , Justin Bedo 1 2 , Matthew Wakefield 1 2 , Hasan Mirza 4 , Cassandra Vandenberg 1 2 , Gayanie Ratnayake 5 , Genevieve Dall 1 2 , Ratana Lim 1 , John Weroha 6 , Iain McNeish 4 , Tony Papenfuss 1 2 7 , Clare Scott 1 2 5 7
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. The University of Melbourne, Melbourne, VIC, Australia
  3. Monash Health, Monash University, Clayton, VIC, Australia
  4. Imperial College London, London, UK
  5. Royal Women's Hospital, Parkville, VIC, Australia
  6. Mayo Clinic, Rochester, Minnesota, USA
  7. The Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Ovarian carcinosarcoma (OCS) is the most lethal gynaecological cancer1,2. Evidence-based treatment is limited to first-line platinum-based chemotherapy and most patients develop lethal, relapsed disease within one year of treatment2,3. Therefore, identifying new therapeutic strategies is vital. OCS are heterogeneous, with both epithelial (carcinoma) and mesenchymal (sarcoma) components proposed to exist in a state of stable epithelial-to-mesenchymal transition (EMT)2,4. 

We have undertaken the first comprehensive genomic analysis of OCS, with dissection of the carcinoma and sarcoma components. This showed that these tumours are monoclonal and genomically largely indistinguishable from high-grade serous ovarian carcinoma (HGSOC). RNA sequencing of the dissected components indicated that the carcinoma components are more mesenchymal than pure HGSOC, indicating these tumours may have been primed to undergo sarcomatous transformation early in carcinogenesis via EMT. We hypothesise that the high EMT scores observed in these tumours explain why OCS is less responsive to standard therapies than HGSOC. Therefore, in our quest to identify new treatments for OCS we are focusing on drugs that target EMT.

We used a genetically-engineered mouse model of OCS to test the efficacy of microtubule-targeting drugs, including eribulin, which has been shown to reverse EMT characteristics. We demonstrated that vinorelbine and eribulin were more effective than standard-of-care platinum chemotherapy. Eribulin significantly reduced adhesion and invasion, accompanied by an impressive reduction in expression of the mesenchymal markers ZEB1, N-cadherin, and Vimentin, as well as in HMGA2, a key feature of OCS5.

We also characterised a cohort of molecularly annotated OCS patient-derived xenograft (PDX) models. Anti-microtubule agents were again more effective than platinum chemotherapy. Importantly, after a single dose of eribulin, a decrease in the expression of HMGA2 and other mesenchymal markers was observed.

RNAseq analysis indicated that eribulin treatment significantly reduced the expression of genes involved in the mevalonate (MVA) pathway and significantly up-regulated genes involved in activation of immune responses. We demonstrated that eribulin treatment resulted in an accumulation of intracellular cholesterol, causing cells to switch off the MVA pathway to prevent more cholesterol being synthesised. Accumulation of intracellular cholesterol alters membrane characteristics, which has previously been shown to reverse EMT characteristics6. Eribulin treatment also reduced the expression of N-MYC in OCS PDX models, which has also previously been linked to MVA pathway regulation in neuroblastoma7. In addition, eribulin treatment induced infiltration of CD8+ T-cells into tumours. These mechanisms of action are completely novel findings for eribulin, not only supporting eribulin for the treatment OCS, but suggesting eribulin/immunotherapy combinations may demonstrate even greater efficacy. As such, we have designed the international EPOCH trial, Eribulin and Pembrolizumab in Ovarian Carcinosarcoma, to improve treatment of this aggressive cancer.

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