Flash Talk & Poster Presentation 31st Lorne Cancer Conference 2019

Identifying novel treatment options for women with aggressive, therapy-resistant ovarian carcinosarcoma     (#122)

Holly E Barker 1 2 , Gwo Yaw Ho 1 3 4 , Elizabeth Kyran 1 , Kristy Shield-Artin 1 2 , Cassandra Vandenberg 1 2 , Justin Bedo 1 2 , Jan Pyman 3 , John Weroha 5 , Matthew Wakefield 1 2 , Ronny Drapkin 6 , Tony Papenfuss 1 4 , David Bowtell 4 , Clare Scott 1 3 4
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. The University of Melbourne, Melbourne, VIC, Australia
  3. Royal Women's Hospital, Parkville, VIC, Australia
  4. The Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  5. Mayo Clinic, Rochester, Minnesota, USA
  6. The University of Pennsylvania, Philadelphia, USA

Ovarian carcinosarcoma (OCS) is the most lethal gynaecological cancer (1,2). Evidence-based treatment is limited to first-line platinum-based chemotherapy and most patients develop lethal, relapsed disease within one year of treatment (2,3). 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 generated a genetically-engineered mouse model (GEMM) of OCS, driven by over-expression of Lin28b and inactivation of p53 in fallopian tube (FT) secretory epithelial cells, and six OCS patient-derived xenograft (PDX) models, with varying ratios of carcinoma and sarcoma. These models were all resistant to cisplatin, the current standard-of-care therapy for OCS, as is seen in the clinic, however, exhibited varying sensitivities to microtubule drugs, including the novel chemotherapeutic eribulin, which has previously been shown to reverse EMT. Interestingly, all of the tumours exhibited a reduction in expression of the EMT marker HMGA2, which is expressed in 60% of OCS tumours, following eribulin treatment. Moreover, a cell line generated from the GEMM displayed reduced branching in 3D collagen cultures, adhesion to collagen and invasion through extracellular matrix following treatment with eribulin, further supporting its role in reversing EMT.

We have used our GEMM-OCS cell line to screen a drug library of 4000 compounds, and have identified a number of potential single agent therapies, as well as eribulin-based combination therapies for further analysis in our pre-clinical models. Of particular interest are the HMG-CoA reductase inhibitors, which may play a role in reversal of EMT and inhibition of metastasis. We have also carried out a CRISPR screen to predict future mechanisms of resistance to eribulin. Due to the biphasic nature of carcinosarcomas, eribulin-based combination therapies will likely be more efficacious than the current standard-of-care treatments available for women with this aggressive disease.

  1. 1) Mano, M.S., et al. Current management of ovarian carcinosarcoma. Int J Gynecol Cancer 17, 316-324 (2007).
  2. 2) Rauh-Hain, J.A., Birrer, M. & Del Carmen, M.G. "Carcinosarcoma of the ovary, fallopian tube, and peritoneum: Prognostic factors and treatment modalities". Gynecol Oncol 142, 248-254 (2016).
  3. 3) Shylasree, T.S., Bryant, A. & Athavale, R. Chemotherapy and/or radiotherapy in combination with surgery for ovarian carcinosarcoma. Cochrane Database Syst Rev, CD006246 (2013).
  4. 4) Zhao, S., et al. Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition. Proc Natl Acad Sci U S A 113, 12238-12243 (2016).