Background: Mucinous ovarian cancer (MOC) is a rare epithelial ovarian cancer. There are currently no adjuvant therapies for MOC that reliably improve patient outcome, therefore new approaches are needed. MOC genetic alterations and resulting proteins are candidates for targeted molecular therapies. About a quarter of MOC carry high-level ERBB2 (HER2), and early case reports were promising for anti-HER2 targeted agents such as trastuzumab. We hypothesized that the ADC trastuzumab deruxtecan (T-DXd) will show efficacy in models of MOC expressing HER2.
Aims: In this study, we aim to test an antibody drug conjugate (ADC) carrying a drug component that MOC is sensitive to that targets an overexpressed protein. In addition, MOC with other genetic events may be sensitive to relevant targeted therapies.
Methods: We performed high throughput pre-clinical testing of existing and targeted therapies in three representative cell lines (MCAS, JHOM-1, RMUG-S) as well as organoid models. Cell lines were dosed with selected drugs and cell viability determined after 96 hours by staining with DAPI. Organoid viability was assessed using CellTiterGlo and Hoechst staining. HER2 expression was assessed by immunohistochemistry.
Results: We found that the topoisomerase I inhibitors topotecan and irinotecan were effective chemotherapies in cell lines and organoids, including ORG49 and ORG66 with ERBB2 amplification. This suggested that deruxtecan drug conjugates could be effective in MOC. We evaluated HER2 protein overexpression in our MOC models (patient tumors, cell lines, organoids and patient-derived xenografts) and found that there are two with HER2 3+ staining, and at least one with 2+. One HER2 3+ and one HER2 2+ model were successfully transferred to mouse xenografts in immunocompromised mice (NSG). A pilot study testing 86 small molecule therapies in cell lines and 1 organoid line identified other candidates that will be correlated to genetic events. A larger screen will be conducted in the future.
Conclusions: Antibody drug conjugates (ADCs) present an exciting opportunity to improve outcomes in MOC. In the future we will test out HER2+ models for response to T-DXd. Providing pre-clinical evidence of efficacy of this agent will open the door for treatment for women with advanced MOC.