Methylthioadenosine (MTA) increases the therapeutic window of AG2037 in MTAP-deficient tumors

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Due to inherent resistance of human cancers, the clinical response rate for most of these tumors is often low even at the MTD. One strategy to increase the success of anticancer agents in these situations is to increase the administered dose. However, toxic side effects of these agents often prevent such an increase, focusing some drug development efforts on ways to rescue normal cells from toxic side effects. Tumors often demonstrate genomic instability often resulting in gene silencing. The absence of specific genes products in tumors may result in a unique opportunity to develop new treatment strategies. An example of such an strategy would be the loss of purine salvage in tumors, e.g the MTAP purine salvage pathway, combined with the chemical inhibition of de novo purine synthesis, e.g. by the antifolate GARFT inhibitor AG2037. The genomic difference in MTAP status between MTAP-deficient tumors and normal tissue allows the combination of an agent that inhibit de novo purine synthesis with an agent such as MTA, the natural substrate for MTAP, to potentially rescue normal cell from toxic side effects and increase the therapeutic window of the inhibitor. In this study the rescue effect of MTA in mice bearing an MTAP-deficient tumor on the toxicity and antitumor activity of AG2037 were investigated. In one experiment mice bearing the BxPC-3 human pancreatic xenograft were dosed with AG2037 qdx4 with and without MTA bid q8d. Adding MTA to the administration of AG2037 decreased the toxicity of AG2037 by 16-fold while not affecting the antitumor activity at each dose level of AG2037, increasing the therapeutic window of AG2037 by 16-fold. In another experiment mice bearing the PANC-1 human pancreatic xenograft were dosed with AG2037 q3dx4 with and without MTA bid q14d. The AG2037-induced weight loss in the mice was reduced 2-fold by administration of MTA while the antitumor activity of AG2037 was not affected. Thus MTA selectively reduced the toxicity of AG2037 without affecting its activity against MTAP-deficient tumors, increasing the therapeutic window.