Abstract 1074: Improving efficacy of microtubule inhibitors in the treatment of high-grade serous ovarian cancer and ovarian carcinosarcoma

The high mortality (>80%) seen in high-grade serous ovarian cancer (HGSOC) highlights the unmet clinical need for treatments capable of producing long-term sustained responses. The related cancer, ovarian carcinosarcoma (OCS), has even poorer survival rates, which is due in part to being a rare cancer but also because of its unique phenotype. OCS are composed of both epithelial (carcinoma) and mesenchymal (sarcoma) components and molecular analysis has shown that most OCS are monoclonal and are derived from a common progenitor with sarcomatous transformation occurring by a stable epithelial-to-mesenchymal transition (EMT) process involving reprogramming of gene expression. Paclitaxel is an effective microtubule-stabilizing drug that is used in the treatment of HGSOC and OCS, however, resistance to platinum-taxane treatment usually occurs within 2-3 years and earlier in many OCS. We have been investigating the microtubule inhibitors, vinorelbine and eribulin, which each bind to distinct regions of microtubules and have a different mechanism of inhibition compared to paclitaxel. Eribulin has also been shown to reverse EMT, inducing vasculature remodeling and changes to the tumor-immune microenvironment. This dual activity of eribulin provides greater potential for improved efficacy in the clinic. Focusing on platinum resistant/refractory patient-derived xenografts (PDX) of HGSOC and OCS we assessed response to paclitaxel, vinorelbine and eribulin treatment and observed that around 50% of PDX were sensitive (HGSOC 8/13, 8/13 and 4/8 respectively; OCS 3/6 for all treatments). To deliver higher doses of drug to tumors but also limit toxicity, antibody-drug conjugates (ADCs) are being developed. MORAb-202 is an eribulin-anti-folate receptor alpha (FRα) ADC. It has been reported that 80-90% of HGSOC express FRα and in our HGSOC PDX cohort 14/15 (93%) were positive. However, only 1/5 (20%) OCS model showed any FRα and this was restricted to epithelial glandular structures, Citation Format: Cassandra J. Vandenberg, Gwo-Yaw Ho, Ksenija Nesic, Elizabeth M. Swisher, Sean M. Grimmond, Matthew J. Wakefield, Holly E. Barker, David D. Bowtell, Clare L. Scott. Improving efficacy of microtubule inhibitors in the treatment of high-grade serous ovarian cancer and ovarian carcinosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1074.