Abstract 5466: Efficacy of ASC60, an oral fatty acid synthase inhibitor, in two tumor mouse models

Abstract

Abstract Background: Fatty acid synthase (FASN) is a key enzyme controlling endogenous lipid biosynthesis and overexpressed in many cancers. Studies have shown that FASN inhibition can disrupt lipid synthesis in tumor cells and disrupt tumor-associated signal transduction, suggesting FASN inhibition can serve as a potential treatment for cancer. Here we report the in vivo efficacy data of ASC60, a small molecular FASN inhibitor, either as a single agent or in combination with mouse programmed cell death-1 (mPD-1) antibody in two tumor mouse models. Methods: In the MC38 mouse model, mice were inoculated subcutaneously with MC38 cells. When the average tumor volume reached approximately 62 mm3, mice were treated with ASC60 (60, and 100 mg/kg) or vehicle once a day (QD) for 3 weeks in combination mPD-1 antibody twice a week (1 mg/kg, BIW) for 2 weeks. In patient derived orthotopic xenograft (PDOX) brain metastasis mouse model, luciferase labelled breast cancer cells (LD1-2009-362541-Luc) were transplanted into the brain of nude mice. Tumor volumes were estimated by the luciferase reporter signal. When the average signal reached 4.12X107 photon/sec, mice were treated with ASC60 (20, 60, and 100 mg/kg) or vehicle QD for 4 weeks. In both mouse models, body weights and tumor volumes were measured regularly, and tumor growth inhibitions (TGI) of different groups were compared. Results: All animals showed a gradually increase in body weight during the study and no significant difference of body weight or body weight change was found among different groups. In the MC38 colon cancer mouse model, mice treated with ASC60 (60 or 100 mg/kg) in combination with mPD-1 antibody showed higher TGI values compared to those treated with mPD-1 alone (91.86%, 99.88% vs 89.84%) on Day 13, indicating combination with ASC60 would enhance the antitumor activity of mPD-1 antibody. In PDOX mouse model, mice treated with ASC60 (20, 60, and 100 mg/kg) showed dose dependent TGI values of 10.83%, 36.95% and 49.21% on Day 13 and of 6.46%, 21.27% and 30.47% on Day 27, respectively. ASC60 also showed a significant improvement in life span (51.5 days in ASC60 60 mg/kg vs 39 days in vehicle control). Conclusion: Previous in vitro testing showed that inhibition of palmitate synthesis by ASC60 was 137-fold lower in mouse than in human (IC50: 2.05 µM in mouse vs 0.015 µM in human). However, results of the present studies showed that ASC60 could suppress tumor growth and/or expand lifespan in the two tumor mouse models either alone or in combination with mPD-1 antibody. ASC60 will possibly demonstrate better efficacies in human. Citation Format: Jinzi J. Wu, Handan He. Efficacy of ASC60, an oral fatty acid synthase inhibitor, in two tumor mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5466.