Abstract 18: Doubled lifespan in APCMin/+mice by targeting MTAP

Humans with Familial Adenomatous Polyposis (FAP) have increased risk of colon cancer. Mice with the APC Min/+ mutation provide an animal model of FAP. Interruption of epigenetic control by preventing salvage of S-adenosylmethionine from 5′-methylthioadenosine (MTA) was tested as a potential FAP therapy. 5′-Methylthioadenosine phosphorylase (MTAP) catalyzes the phosphorolysis of MTA to adenine and methylthioribose-1-phosphate for methionine recycling. The effect of MTDIA, a transition state analogue of MTAP, was tested as an oral agent in APC Min/+ mice. Survival analysis with 10, 20 and 30 mg/kg/day oral doses of MTDIA showed a 2-fold increase in mouse lifespan at the optimal 20 mg/kg/day dose. Metabolomic analysis (mouse liver) showed significant changes in metabolites relevant to methionine metabolism. The >4-fold increase in MTA, confirmed the physiologic target. Histologic analysis of intestinal tissue revealed slowed tumor progression in treated mice. RNAseq and Western blots provide additional information about the consequences of MTAP inhibition. Citation Format: Ross S. Firestone, Mu Feng, Vern L. Schramm. Doubled lifespan in APC Min/+ mice by targeting MTAP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 18.