Abstract 5998: In vitro and in vivo anticancer effects of D/L-alpha-metyrosine (SM-88), a novel metabolism-based therapy

Introduction: D/L-alpha-metyrosine (SM-88, racemetyrosine) is a clinical stage chemically modified racemic amino acid therapy with broad anticancer activity in patients across 15 different indications. While amino acid metabolism has been leveraged in oncology imaging for decades, SM-88 offers a novel therapeutic approach to selectively disrupt cancer cells. This study explored phenotypic and mechanistic effects of exposing cancer cells to D/L-alpha-metyrosine as well as potential immunomodulation of the in vivo tumor microenvironment related to tyrosine hydroxylase inhibition and catecholamine depletion. Methods: In vitro experiments were conducted in a range of human and mouse cancer cell lines, including MCF-7, 4T1, HCT116, CAPAN2, PAN02, PANC01. The effect of SM-88 methyl-ester (SM-88 ME) alone on viability, apoptosis, migration/invasion, protein synthesis inhibition, autophagy, cell cycle arrest, and ROS generation was assessed. In vivo experiments included xenograph studies of HCT116 with monotherapy consisting of either IP injections up to 200 mg/kg/day of SM-88 ME, or orally administered SM-88 up to 324 mg/kg/day. Orthotopic xenographs of 4T1 and PAN02 models using monotherapy doses up to 200 mg/kg/day are ongoing. Ongoing immunohistochemistry and flow cytometry is focused on correlation with LAT1 expression and efficacy, alteration in macrophage polarization (M1/M2 ratio), Tregs, and various T cell populations in the tumor microenvironment. Results: Exposure to SM-88 ME exhibited a dose dependent increase in ROS, as well as decreases in caspase 3/7 activation. An increase in ROS following exposure to SM-88 ME was also observed in PAN02 cells. Similar decreases in caspase 3/7 activation were observed in CAPAN2, HCT116, and MCF7 cells. Interestingly, across a variety of cell lines including PAN02, PANC1, and 4T1 cell morphology changes suggested the formation of autophagic vacuoles. Viability across all cell lines was reduced in a dose and time dependent manner. In a mouse HCT116 SC xenograft model, mice receiving 324 mg/kg/day SM-88 ME showed significantly reduced tumor size compared to control mice. Additional in vitro and in vivo experiments are ongoing. Conclusions: The importance of amino acid metabolism in cancer has gained greater awareness over the past decade, however potential therapeutic approaches in this area remain limited. SM-88 has been dosed in over 180 cancer patients with encouraging efficacy and safety findings to date. Early data suggest increases in ROS generation and decreases in apoptosis may occur in certain cancer types (PAN02 pancreatic cancer), suggesting a shift away from apoptosis and towards autophagy. Potential immune modulatory effects of SM-88, including alterations in macrophage polarization related to tyrosine hydroxylase inhibition and subsequent reductions in catecholamine production are being examined. Citation Format: Alexander Vandell, Jonathan Eckard, Steve Hoffman, Giuseppe Del Priore, Martin Fernandez-Zapico. In vitro and in vivo anticancer effects of D/L-alpha-metyrosine (SM-88), a novel metabolism-based therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5998.