Poster Presentation 31st Lorne Cancer Conference 2019

Mesenchymal transformation as a potential target of the microtubule dynamic inhibitors, eribulin, in fallopian tube derived/ovarian carcinosarcoma (#201)

Gwo Yaw Ho 1 2 3 , Cassandra Vandenberg 1 , Ennis Darren 4 , Elizabeth Kyran 1 , Ellen Mathieson 1 , Olga Kondrashova 1 , Kristy Shield-Artin 1 , Silvia Stoev 1 , Kathy Barber 1 , Jan Pyman 2 , Jackie Collett 2 , Anne Hamilton 2 3 , Orla McNally 2 , Matthew J Wakefield 1 , Ronny Drapkin 5 , Tony Papenfuss 1 , David Bowtell 3 , Iain A McNeish 4 , Susanna L Cooke 6 , Holly Barker 1 , Clare Scott 1 3
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Royal Women’s Hospital, Melbourne, VIC, Australia
  3. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  4. Imperial College London, London, UK
  5. Penn Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA
  6. The Scottish Genomes Partnership, Edinburgh

Fallopian tube-derived ovarian carcinosarcoma (FT/OCS) is an aggressive rare gynaecologic cancer with limited treatment options1. FT/OCS contains both epithelial (carcinoma) and mesenchymal (sarcoma) components and is proposed to arise from a single epithelial progenitor that de-differentiates to form the mesenchymal element, suggesting that carcinosarcoma is an example of stable epithelial-to-mesenchymal transition (EMT)2.  HMGA2 over-expression is common in both HGSOC and FT/OCS and is an established downstream target of the MYCN/LIN29B/let-7 pathway axis3. This pathway is of therapeutic relevance for the C5/Stem-A subtype of HGSOC which shows sensitivity to microtubule inhibitors (vincristine and vinorelbine), suggesting that microtubule inhibitors may also show efficacy in FT/OCS4.

Here we demonstrate in vivo efficacy for both vinorelbine and the less toxic microtubule inhibitor, eribulin mesylate, in a genetically engineered mouse model (GEMM) and patient derived xenograft (PDX) models of FT/OCS (5 PDX models; KM survival probability p < 0.02). DNA sequencing using a 275-gene panel including SNV analysis of 17 micro-dissected human FT/OCS showed few mutational differences between carcinoma and sarcoma elements, with 100% SNV concordance in 50% of cases analysed, suggesting that differences between elements are not genomic. However, the copy number profiles did differ in most cases and gene expression analysis is on-going. Opal staining of FT/OCS tumours indicated that they are cold tumours with few infiltrating lymphocytes. As eribulin has been shown to modulate the immune microenvironment in breast cancer5, we have designed a clinical trial, EPOCH, to deliver eribulin and pembrolizumab for women with OCS.

The findings presented here provide pre-clinical evidence to support eribulin for clinical trial development in FT/OCS and uterine CS, to provide a new treatment options for women with these rare and aggressive gynaecological cancers.

  1. Rauh-Hain, J.A., Birrer, M. & del Carmen, M.G., 2016. “Carcinosarcoma of the ovary, fallopian tube, and peritoneum: Prognostic factors and treatment modalities.” Gynecologic Oncology, 142(2), pp.248–254
  2. Zhao, S. et al., 2016. Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition. Proceedings of the National Academy of Sciences, 113(43), pp.12238–12243
  3. Helland, Å. et al., 2011. Deregulation of MYCN, LIN28B and LET7 in a Molecular Subtype of Aggressive High-Grade Serous Ovarian Cancers. PLoS ONE, 6(4), pp.e18064–20
  4. Tan, T.Z. et al., 2013. Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer. EMBO Molecular Medicine, 5(7), pp.1051–1066
  5. Tolaney, S. et al., 2017. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. European Journal of Cancer, 72(Supplement 1), p.S16