Abstract PO023: Preliminary data on metformin therapy in DICER1-deleted endometrial cancer

Abstract

We created and characterized the first genetically engineered mouse model of poorly-differentiated endometrial adenocarcinoma (dcKO, Pgr^Cre; Pten^flox/flox; Dicer1^flox/flox). As an additional novel model system, using CRISPR-Cas9, we created and characterized an isogenic cell line with the deletion of DICER1 (DICER1 ^−/− Ishikawa cells). Transcriptomic profiling across mouse and human models revealed activated pathways, including AMP kinase and insulin signaling. Ingenuity Pathway Analysis revealed metformin as a likely therapeutic target. Previous studies have suggested that metformin may be useful for preventing and treating endometrial cancer in women. However, recent clinical trials showed combined treatment of metformin with paclitaxel and carboplatin was not significantly associated with increased progression-free survival or overall survival for advanced or recurrent endometrial cancer. To test the effects of metformin in our mouse model, female mice received ad lib water containing metformin (5 mg/mL) or water beginning at weaning. Survival studies showed worse survival for well-differentiated endometrial adenocarcinoma (Pten cKO, Pgr^Cre; Pten^flox/flox; Dicer1^+/+) with treatment with metformin (P=0.007), while there was no difference for dcKO mice treated with metformin. Similarly, in vitro studies showed that the treatment of DICER1 ^−/− Ishikawa cells treated with metformin did not affect cellular proliferation. Our in vivo and in vitro model systems represent important tools to study metformin and other therapeutics for rare yet aggressive endometrial cancers. Citation Format: Xiyin Wang, Robert Emerson, Russell Broaddus, John Lydon, Francesco DeMayo, Shannon M. Hawkins. Preliminary data on metformin therapy in DICER1-deleted endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO023.