Poster Presentation 37th Lorne Cancer Conference 2025

Drug screening in organoid models identifies novel combination therapies for the treatment of ovarian carcinosarcoma   (#107)

Andrew Farrell 1 , Genevieve Dall 1 , Cassandra Vandenberg 1 2 , Kristy Shield-Artin 1 2 , Elizabeth Kyran 1 3 , Gayanie Ratnayake 4 , Justin Bedo 1 2 , Jocelyn Penington 1 , Tony Papenfuss 1 2 5 , Clare Scott AM 1 2 4 5 , Holly Barker 1 2
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. The University of Melbourne, Melbourne, VIC, Australia
  3. Cancer Research UK Cambridge Institute, The University of Cambridge, Cambridge, UK
  4. Royal Women's Hospital, Parkville, VIC, Australia
  5. The Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Ovarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options1. OCS are composed of both epithelial (carcinomatous) and mesenchymal (sarcomatous) components1. We, and others, have provided recent evidence that these tumours arise from a single progenitor cell, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT)2. These tumours also commonly harbour up-regulation of the N-MYC/LIN28B pathway, resulting in expression of the early development gene HMGA23. We have previously shown that eribulin can reverse EMT and induce recruitment of CD8-positive T-cells in our preclinical models of OCS, which led to the development of the EPOCH trial (NCT05619913)2.

Here, we performed a drug library screen (3885 compounds with FDA-approval or proven activity) alone and in combination with cisplatin (current standard OCS treatment is platinum-based) or eribulin in a mouse OCS cell line. We validated the top hits in our unique human OCS cell lines and organoid models, with a focus on drugs that could potentially reverse EMT and/or target N-MYC. The most effective combination therapies were then tested in OCS PDX models in vivo.

Cisplatin combined with an HSP90 inhibitor or a WEE1 inhibitor were the most effective combinations in OCS organoid models, however, both combinations showed greater efficacy in our two HGSOC organoid models. Eribulin combined with an EGFR inhibitor (EGFRi) or a MEK inhibitor (MEKi) were the most effective combinations in OCS organoid models. Eribulin-based combination therapies were more effective in the OCS PDX models in vivo, however, only modest improvements in survival were observed. In addition, two of the models tested for response to the eribulin plus EGFRi combination were later found to have resistance mechanisms, such as high ABCB1 expression (encoding the multi-drug resistance protein) and a KRAS constitutive activation mutation (a known resistance mechanism to EGFRi). The KRAS mutant model was found to respond to a combination of an EGFR/RAF inhibitor with a MEKi.

The results we present here indicate that eribulin-based combination therapies may improve patient outcomes for these aggressive malignancies, however, the molecular characteristics of the tumour should be taken into account when designing treatment approaches.

  1. Barker, H.E. & Scott, C.L. Genomics of gynaecological carcinosarcomas and future treatment options. Semin Cancer Biol (2020).
  2. Ho, G.Y., et al. Epithelial-to-mesenchymal transition supports ovarian carcinosarcoma tumorigenesis and confers sensitivity to microtubule-targeting with eribulin. Cancer Res (2022).
  3. Mahajan, A., et al. HMGA2: a biomarker significantly overexpressed in high-grade ovarian serous carcinoma. Mod Pathol 23, 673-681 (2010).