Obese patients with certain cancers face a greater risk of dying from their cancer compared to non-obese patients. Obesity may contribute to cancer progression via multiple mechanisms: increased leptin, decreased adiponectin, increased adipose tissue estrogen, elevated insulin (secondary to peripheral insulin resistance), increased cytokines, and alteration of the TIME which suppresses host anti-tumor immune responses. Small molecule MetAP2 inhibitors have previously shown clinical anti-tumor activity. However, clinical development in some cases (e.g. TNP-470) has been altered CNS toxicity. SDX-7320 is a polymer-drug conjugate of a novel fumagillin-derived MetAP2 inhibitor (SDX-7539) attached via a cleavable linker to a hydroxypropylmethacrylamide (HPMA) backbone. This is intended to limit CNS penetration and reduce CNS toxicity relative to small molecules. SDX-7320 was tested ± 5-FU in a syngeneic model of post-menopausal, obesity-accelerated breast cancer. Ovariectomized C57Bl/6 mice were fed a high-fat diet (to induce obesity) or low-fat diet for 16 weeks prior to injection of EO771 tumor cells into the mammary gland. Tumors in obese mice grew significantly faster than in low fat-fed (normal) mice. SDX-7320 (8 mg/kg, SC, Q4D) significantly attenuated tumor growth in normal and obese mice relative to vehicles (-33% and -43% respectively). 5-FU (10 mg/kg, IP, 2X/week) had no effect on tumor growth in normal or obese mice, while the combination of 5-FU with SDX-7320 inhibited tumor growth in obese mice greater than SDX-7320 alone (-61% vs -43% respectively), suggestive of a synergistic interaction. In a separate study, the effect of SDX-7320 on the EO771 TIME in obese versus normal-weight mice was assessed. Tumors in obese mice grew significantly faster than in normal mice. SDX-7320 (24 mg/kg, SC, Q4D) decreased tumor growth in both normal and obese mice (-53% and -52% change in tumor volume relative to lean and obese vehicle groups, respectively). SDX-7320 also reduced the immunosuppressive state of the TIME in obese mice. Relative to tumors from untreated mice, MDSC content (flow cytometry), Arginase 1 staining (by IHC) and FoxP3 staining (by IHC) were all decreased. Analysis of cytokines showed that IL-10 was elevated in plasma of obese mice relative to normal mice, and SDX-7320 significantly reduced the plasma levels of IL-10 in obese mice. SDX-7320 exerted favorable effects on the TIME in a model of post-menopausal obesity-accelerated breast cancer suggesting it may potentiate the efficacy of immunotherapy in breast cancer. SDX-7320 is being developed to treat cancers whose growth is accelerated by obesity and metabolic dysfunction. Now nearing completion of Phase I (NCT02743637), further clinical trials with SDX-7320 in combination with other therapies are planned for 2019.

Citation Format: Peter Cornelius, Benjamin Mayes, Sara Little, Andrew Slee, David Turnquist, James Shanahan, Bradley Carver. A novel polymer-conjugated methionine aminopeptidase 2 (MetAP2) inhibitor SDX-7320 inhibits the growth of EO771 mammary gland tumors and ameliorates the immunosuppressive tumor immune micro-environment (TIME) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1226.