Abstract C031: Evexomostat (SDX-7320), a methionine aminopeptidase type 2 (METAP2) inhibitor, inhibits obesity-accelerated tumor growth and stimulates weight loss in obese mice

Abstract Obesity and diabetes are associated with worse prognosis for numerous malignancies. In independent non-clinical models, small molecule inhibitors of METAP2 inhibit tumor growth and induce weight loss but effects on obesity-accelerated tumor growth are unknown. SDX-7320 is a novel, optimized METAP2 inhibitor. Our first objective was to determine the effects of SDX-7320 on obesity and insulin resistance in DIO mice. Our second objective was to evaluate whether targeting METAP2 could attenuate obesity-accelerated tumor growth in DIO mice and to define underlying mechanisms. The final aim was to compare the anti-tumor activity of SDX-7320 vs. tirzepatide (TZP), a highly effective weight loss agent in DIO tumor-bearing mice. The anti-obesity activity of SDX-7320 was evaluated in male diet-induced obese (DIO) mice, following subcutaneous administration every four days. The insulin-sensitizing activity of SDX-7320 was assessed in male DIO mice using an insulin-tolerance test, following a single subcutaneous injection of SDX-7320. The effect of SDX-7320 on obesity-accelerated tumor growth was tested in male mice (lean and DIO) with B16F10 tumors, female ovariectomized mice (lean and DIO) with EO771 tumors, and male mice (lean and DIO) with MC38 tumors. The anti-tumor and anti-obesity efficacy of SDX-7320 and TZP were compared in DIO mice with MC38 tumors. Effects of these compounds on obesity were assessed by measuring body weight, adipose tissue mass and plasma adipokines. RNA-Seq was carried out to define the effects of SDX-7320 on MC38 tumors from lean and DIO mice. Untargeted metabolomics was used to compare the effects of SDX-7320 and TZP. SDX-7320 elicited weight loss in obese mice accompanied by increased insulin sensitivity, decreased plasma leptin, and increased plasma adiponectin. SDX-7320 significantly attenuated the growth of established tumors in all models tested, with greater inhibition in obese versus lean mice. Treatment with SDX-7320 led to significant alterations in MC38 tumor gene expression: increased interferon alpha- and gamma-response pathways and decreased cell cycle pathways. To assess the contribution of weight loss to anti-tumor activity, the effects of SDX-7320 and TZP were compared in DIO mice with MC38 tumors. Both agents inhibited obesity-accelerated tumor growth, but SDX-7320 was significantly more efficacious despite causing less weight loss. Plasma metabolomics revealed non-overlapping effects, consistent with distinct mechanisms of action for each agent. The potent anti-tumor activity of SDX-7320 in obesity-accelerated cancers is attributed to both direct and indirect effects, including cell cycle inhibition, immune stimulation, and favorable systemic metabolic changes occurring in association with weight loss. Since GLP-1 receptor expression in MC38 tumors was undetectable, our results with TZP support the concept that excess adipose tissue indirectly promotes tumor growth. The direct effects of SDX-7320 on tumors combined with reductions in adipose tissue resulted in superior anti-tumor activity versus TZP. Citation Format: Peter Cornelius, Benjamin A. Mayes, Andrew J. Dannenberg, Pierre J. Dufour, Sara Little, Douglas V. Guzior, John S. Petersen, James M. Shanahan, Bradley J. Carver. Evexomostat (SDX-7320), a methionine aminopeptidase type 2 (METAP2) inhibitor, inhibits obesity-accelerated tumor growth and stimulates weight loss in obese mic} [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr C031.