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.
Highlights
A mouse model of human Familial Adenomatous Polyposis responds favorably to pharmacological inhibition of 5′-methylthioadenosine phosphorylase (MTAP)
The APCMin/+ model is a valuable tool to investigate the efficacy of novel treatments for spontaneously forming Colorectal cancer (CRC), for Familial Adenomatous Polyposis (FAP), and for the tumors that develop in the small intestine of FAP patients following colectomy to eliminate extensive large intestinal tumors[9]
MTAP deletion frequency is more rare in CRC than in other cancers, some CRC cell lines have been shown to have significantly increased MTAP and MAT2A expression, indicating increased reliance on these metabolic pathways15–17. MTAP−/− cancer cell lines have increased levels of MTA, which inhibit the activity of the methyltransferase PRMT5, as a 260 nM inhibitor[18]
Summary
A mouse model of human Familial Adenomatous Polyposis responds favorably to pharmacological inhibition of 5′-methylthioadenosine phosphorylase (MTAP). 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. The anti-cancer effects of MTDIA indicate that increased cellular MTA inhibits PRMT5mediated methylations resulting in attenuated tumor growth. The APCMin/+ mouse model is a well-characterized model of human FAP It involves a loss of function mutation in the APC locus, leading to a genetic predisposition to intestinal adenoma formation in mice[6]. Methythio-DADMe-Immucillin-A (MTDIA), is an 86 pM transition-state analogue inhibitor of MTAP It has demonstrated anti-cancer properties in selected in vitro cancer cell lines and in several in vivo mouse models of human cancers. Inhibition of MTAP in cancers by a specific inhibitor has potential as a sole agent and as an enhancer of new agents designed to target histone, DNA, and intron methylation
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