Evexomostat (SDX-7320), a Methionine Aminopeptidase Type 2 (METAP2) Inhibitor, Stimulates Weight Loss and Inhibits Obesity-Accelerated Tumor Growth

Abstract Obesity and diabetes are associated with worse prognosis for numerous malignancies. Both insulin resistance and altered levels of adipokines may explain the link between obesity and tumor progression. In preclinical models, METAP2 inhibitors induce weight loss and possess anti-tumor activity, but their effects on obesity-accelerated tumor growth are unknown. Here, we investigated the effects of SDX-7320, a novel polymer-conjugated METAP2 inhibitor, on obesity and obesity-accelerated tumor growth. The anti-obesity and metabolic effects of SDX-7320 were evaluated in diet-induced obese (DIO) mice. Pharmacokinetic-pharmacodynamic relationships for SDX-7320 and the active moiety SDX-7539, a fumagillin class METAP2 inhibitor, were assessed in DIO rats. Anti-tumor efficacy of SDX-7320 was assessed in syngeneic models of obesity-accelerated tumor growth. The anti-tumor efficacy of SDX-7320 and tirzepatide, a weight loss agent, were compared in DIO mice with MC38 tumors. Treatment with SDX-7320 stimulated weight loss in obese mice, increased insulin sensitivity, decreased plasma leptin, and increased plasma adiponectin. Pharmacokinetic-pharmacodynamic analysis showed greater anti-obesity efficacy in response to SDX-7320 than SDX-7539. SDX-7320 significantly attenuated obesity-accelerated tumor growth in three different models (B16F10, EO771, MC38). RNA-Seq analysis of MC38 tumors indicated that SDX-7320 suppressed expression of cell cycle genes (decreased G2M checkpoint and E2F target pathways) and increased expression of host immune response genes (elevated interferon alpha- and gamma-response pathways). In obese mice, SDX-7320 led to significantly greater MC38 tumor growth inhibition than tirzepatide, but caused less weight loss. Plasma metabolomics revealed non-overlapping effects of SDX-7320 and tirzepatide, consistent with different mechanisms of action. Taken together, we have shown for the first time that a METAP2 inhibitor attenuates obesity-accelerated tumor growth. Mechanistically, SDX-7320-mediated tumor growth inhibition likely results from both direct anti-tumor effects (given the observed intratumoral changes in the expression of cell cycle and immune response genes), and indirect effects on the host including weight loss, decreased adipose mass, improved insulin sensitivity and normalization of plasma leptin and adiponectin levels. The fact that SDX-7320 caused greater tumor growth inhibition than tirzepatide, yet caused less weight loss, suggests that direct anti-tumor effects significantly contribute to the anti-tumor activity of SDX-7320.