Abstract 4919: Preclinical activity of SDX-7320 in mouse models of obesity and obesity-driven cancer

Abstract

Abstract Cancer patients who are obese face a greater risk of dying from cancer compared to nonobese patients (Calle, 2003). Obesity is believed to contribute to metastasis and progression of cancer via multiple mechanisms: increased secretion of the adipose tissue hormone leptin, decreased secretion of adiponectin, increased production of estrogen in adipose tissue, and elevated insulin (secondary to peripheral insulin resistance) as well as the local effects of inflammatory cytokines (Gucalp, 2016). Small-molecule inhibitors of methionine aminopeptidase type 2 (MetAP2) have previously demonstrated clinical activity in oncology (Kudelka, 1998) as well as obesity/type 2 diabetes (Hughes, 2013; Kim, 2015). However, development of some small-molecule MetAP2 inhibitors has been hampered by CNS side effects (Bhargava, 1999). SDX-7320 is a copolymer-drug conjugate of a novel fumagillin-derived MetAP2 inhibitor (SDX-7539) attached via a cleavable linker to a hydroxypropylmethacrylamide (HPMA) backbone, intended to limit CNS penetration and therefore reduce CNS toxicity. In vitro MetAP2 binding assays showed that SDX-7320 was unable to bind to MetAP2 while SDX-7539 was a potent binder (apparent IC50 = 0.13 nM), indicating that cleavage of SDX-7320 is required for biologic activity. SDX-7539 inhibited proliferation of human umbilical vein endothelial cells (HUVECs) with an apparent IC50 = 0.2 nM. The preclinical efficacy of SDX-7320 was evaluated in mouse models of obesity/insulin resistance and also in syngeneic tumor models coupled with high fat diet-induced obesity (DIO)/metabolic dysfunction. Obesity and insulin resistance were induced in C57Bl/6 mice by feeding them a high-fat diet (HFD) for at least 12 weeks. SDX-7320 was dosed subcutaneously every 4 days (for 28 days) into DIO mice or control mice fed a low-fat diet. SDX-7320 caused significant reduction in body weight and fat mass in obese mice while also reversing insulin resistance relative to controls. In addition, SDX-7320 caused greater reduction in body weight in obese mice relative to lean mice. Circulating levels of leptin and insulin were reduced while levels of adiponectin were increased in response to SDX-7320. In mouse models of obesity-accelerated tumor growth, SDX-7320 was more efficacious in obese relative to lean mice harboring subcutaneous B16F10 melanoma or EO771 mammary gland tumors. These effects occurred without any signs of neurotoxicity. SDX-7320, currently in phase I (solid tumors; all-comers; NCT02743637), is being developed for the treatment of cancers whose progression is accelerated in the setting of obesity and host metabolic dysfunction, termed “metabo-oncology.” Citation Format: Peter Cornelius, John S. Petersen, Benjamin Mayes, David Turnquist, Kimberly Sullivan, Alfred Anderson-Villaluz, Robert Lutz, Sara Little, Andrew Slee, Bradley J. Carver, James Shanahan. Preclinical activity of SDX-7320 in mouse models of obesity and obesity-driven cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4919.