Transition state analogue of MTAP extends lifespan of APCMin/+ mice
Ross S Firestone1,2, Mu Feng1, Indranil Basu3
1Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
Abstract:
A mouse model of human Familial Adenomatous Polyposis responds favorably to pharmacological inhibition of 5'-methylthioadenosine phosphorylase (MTAP). Methylthio-DADMe-Immucillin-A (MTDIA) is an orally available, transition state analogue inhibitor of MTAP. 5'-Methylthioadenosine (MTA), the substrate for MTAP, is formed in polyamine synthesis and is recycled by MTAP to S-adenosyl-L-methionine (SAM) via salvage pathways. MTDIA treatment causes accumulation of MTA, which inhibits growth of human head and neck (FaDu) and lung (H359, A549) cancers in immunocompromised mouse models. We investigated the efficacy of oral MTDIA as an anti-cancer therapeutic for intestinal adenomas in immunocompetent APCMin/+ mice, a murine model of human Familial Adenomatous Polyposis. Tumors in APCMin/+ mice were decreased in size by MTDIA treatment, resulting in markedly improved anemia and doubling of mouse lifespan. Metabolomic analysis of treated mice showed no changes in polyamine, methionine, SAM or ATP levels when compared with control mice but indicated an increase in MTA, the MTAP substrate. Generation of an MTDIA-resistant cell line in culture showed a four-fold amplification of the methionine adenosyl transferase (MAT2A) locus and expression of this enzyme. MAT2A is downstream of MTAP action and catalyzes synthesis of the SAM necessary for methylation reactions. Immunohistochemical analysis of treated mouse intestinal tissue demonstrated a decrease in symmetric dimethylarginine, a PRMT5-catalyzed modification. The anti-cancer effects of MTDIA indicate that increased cellular MTA inhibits PRMT5-mediated methylations resulting in attenuated tumor growth. Oral dosing of MTDIA as monotherapy has potential for delaying the onset and progression of colorectal cancers in Familial Adenomatous Polyposis (FAP) as well as residual duodenal tumors in FAP patients following colectomy. MTDIA causes a physiologic inactivation of MTAP and may also have efficacy in combination with inhibitors of MAT2A or PRMT5, known synthetic-lethal interactions in MTAP-/- cancer cell lines.
Insights
Pharmacological inhibition of 5'-methylthioadenosine phosphorylase (MTAP) with oral Methylthio-DADMe-Immucillin-A (MTDIA) effectively reduced intestinal tumors in a mouse model of Familial Adenomatous Polyposis (FAP). This treatment improved anemia and doubled lifespan, showing potential for colorectal cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Familial Adenomatous Polyposis (FAP) is a genetic disorder predisposing individuals to colorectal cancer.
- 5 -methylthioadenosine phosphorylase (MTAP) is a key enzyme in cellular metabolism, and its inhibition is a potential anti-cancer strategy.
- Methylthio-DADMe-Immucillin-A (MTDIA) is an orally available inhibitor of MTAP.
Purpose of the Study:
- To investigate the efficacy of oral MTDIA in a mouse model of FAP.
- To elucidate the underlying molecular mechanisms of MTDIA's anti-cancer effects.
Main Methods:
- Treatment of APCMin/+ mice (a model for FAP) with oral MTDIA.
- Metabolomic analysis to assess changes in key metabolites.
- Immunohistochemical analysis to evaluate specific protein modifications.
Main Results:
- MTDIA treatment significantly reduced intestinal tumor size in APCMin/+ mice.
- Mice treated with MTDIA showed improved anemia and doubled lifespan.
- Increased levels of the MTAP substrate, 5 -methylthioadenosine (MTA), were observed, correlating with reduced PRMT5-mediated methylation.
Conclusions:
- Oral MTDIA demonstrates significant anti-tumor efficacy in a FAP mouse model.
- MTDIA's mechanism involves MTA accumulation, leading to inhibition of PRMT5-mediated methylation and attenuated tumor growth.
- MTDIA monotherapy holds promise for FAP patients and may be effective in combination therapies targeting MAT2A or PRMT5.
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