Mat2a Inhibitor, Ide397, Displays Broad Anti-Tumor Activity Across A Panel Of Mtap-Deleted Patient-Derived Xenografts.

Background: Approximately 15% of all solid tumors harbor deletions in methylthioadenosine phosphorylase (MTAP) (1). MTAP deficiencies have been reported to sensitize tumor cells to methionine adenosyltransferase 2A (MAT2A) modulation (2). MAT2A synthesizes the universal methyl donor and PRMT5 substrate S-adenosylmethionine (SAM) from methionine. PRMT5 symmetrically di-methylates arginine (SDMA) residues on proteins that are key to genomic integrity and proteostasis. We evaluated the anti-tumor activity of the small molecule MAT2A inhibitor IDE397 in multiple CDX models and in an ongoing study of 45 MTAP-deleted PDX models to inform clinical strategy for a First-in-Human clinical trial evaluating IDE397. Methods: CDX models utilized included the HCT116 isogenic pair and endogenous MTAP-deleted models. A series of dose response and time-course studies were performed to inform the efficacy-PD relationship. SAM was quantified by LC-MS and SDMA was visualized by western blot (WB) and further quantified by immunohistochemistry (IHC). PDX models with MTAP homozygous deletions were selected from bladder, esophageal, gastric, head and neck, NSCLC and pancreatic cancers. MTAP deletion was determined by WES and/or SNP 6.0 microarray and verified by absence of significant mRNA. Tumors were subcutaneously implanted into immunocompromised mice by serial transplantation of tumor fragments. Each PDX model included a vehicle control and an IDE397-treated group (n=5/group). IDE397 was administered orally once per day (QD). Tumor growth inhibition (TGI) was calculated using the formula TGI = (TV controlfinal - TV treatedfinal)/(TV controlfinal - TV controlinitial) x 100. Results: Administration of IDE397 resulted in TGI and/or tumor regression in MTAP-deleted CDX and PDX models. The HCT116 MTAP-deleted CDX model was more sensitive to IDE397 compared to the HCT116 MTAP-WT model. IDE397 produced a dose- and time-dependent modulation of the proximal and distal PD biomarkers SAM and SDMA. SAM was decreased in plasma and tumors irrespective of MTAP status. In contrast, SDMA was selectively modulated in MTAP-null models only. In a NSCLC CDX model, a dose dependent TGI was observed, with the higher doses leading to tumor regression. Anti-tumor activity is observed in MTAP-deleted PDX models, where IDE397 administration has resulted in TGI and tumor regressions. Conclusion: Xenograft studies indicate that IDE397 exhibits anti-tumor activity as a single agent in MTAP-deleted CDX models and in MTAP-deleted PDX models of NSCLC, pancreatic, bladder, head and neck, esophageal and gastric cancer. This data supports the clinical evaluation of IDE397 across a wide range of solid tumor types with MTAP-deletion. References: (1) Beroukhim, R. et al. Nature 2010 Feb 18;463(7283):899-905. (2) Marjon, K. et al. Cell Rep 2016 Apr 19;15(3):574-587. Citation Format: Marcus M. Fischer, Neil Bhola, John Faulhaber, Yevgeniy Freyman, Bing Yao, Zineb Mounir, Mark R. Lackner, Claire Neilan. MAT2A inhibitor, IDE397, displays broad anti-tumor activity across a panel of MTAP-deleted patient-derived xenografts [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 1278.