Abstract 108: Inhibiting methionine aminopeptidase 2 prevents liver fibrosis and hepatocellular carcinoma

Abstract

Background: The methionine aminopeptidase 2 (MetAP2) pathway, a key regulator of angiogenesis progress, has been implicated in common pathologic conditions including diabetes, non-alcoholic steatohepatitis (NASH) and cancer. MetAP2 inhibition suppresses cancer cell proliferation and xenograft tumor growth. In this study we investigated the hypothesis that MetAP2 inhibition can prevent liver fibrosis and hepatocellular carcinoma (HCC) induced with diethylnitrosamine (DEN) in rat models by inhibiting neo-vascularization. Methods: Male Wistar rats received weekly intraperitoneal injections of DEN at 50 mg/kg for 18 weeks. After 8 weeks, rats were randomly assigned to treatment with one of two MetAP2 inhibitors ZGN1345 or ZGN1136 versus control vehicle (n = 10 per group): 1) water (control); or 2) ZGN-1345 (3 mg/kg) by daily gavage; 3) 0.15% DMSO (control); or 4) ZGN-1136 (0.3 mg/kg) by daily subcutaneous injection. All rats were sacrificed at 19 weeks. Serum chemistries were performed to evaluate the liver function. Liver fibrosis was assessed with hydroxyproline measurement, Sirius Red and H&E staining with review by a liver pathologist. Liver tumor nodules were recorded and analyzed with IHC staining. Results: ZGN1345 treatment improved ALT and AST on DEN-induced cirrhosis in rat models. Both inhibitors improved the liver fibrosis, including lowering collagen deposition (hydroxyproline measurement and amount of collagen measured with Sirius Red staining) and improving the Ishak fibrosis score. Both inhibitors reduced the number of tumor nodules and suppressed PCNA expression in the liver. More importantly, both inhibitors suppressed neo-vascularization and angiogenesis by inhibiting VEGF expression. Conclusions: MetAP2 inhibitors ZGN1345 and ZGN1136 effectively prevent DEN-induced liver fibrosis and HCC in rat models, potentially by inhibiting neo-vascularization. These data suggest that inhibition of MetAP2 may represent a new prevention strategy for HCC. Table. Effect of ZGN1345 and ZGN1136 on rat liver fibrosis and HCC.GroupsASTALTHydroxyprolineCollagen (%)Fibrosis score rateNodule numbers (>5 mm)PCNA expressionVEGF expressionWater (Control), PO100.0 ± 35.5100.0 ± 29.5100.0 ± 39.913.1 ± 3.8F4:25.0%,F3:37.5%,F2:37.5%27.4 ± 14.2100.0± 36.4100.0 ± 44.6ZGN-1345, PO45.5 ± 11.1 ***44.7 ± 14.3 ***36.9 ± 10.5 ***4.7 ± 2.2 ***F2:11.1%,F1:77.8%,F0:11.1%5.7 ± 3.9 ***40.1 ± 13.3 ***21.9 ± 9.8 ***0.15% DMSO (Control), SC100.0 ± 28.1100.0 ± 21.1100.0 ± 63.99.2 ± 3.5F3:42.9%,F2:42.9%,F1:14.3%41.1 ± 40.2100.0 ± 22.8100.0 ± 29.4ZGN-1136, SC89.1 ± 11.3107.1 ± 37.242.9 ± 8.6 *2.9 ± 1.7 **F2:14.3%,F1:42.9%,F0:42.9%4.1 ± 2.8 *29.9 ± 9.4 ***52.3 ± 21.6 *** Citation Format: YONGTAO WANG, Mozhdeh Sojoodi, Guoliang Qiao, Zenan Lin, Stephen C. Barrett, Lawrence Zukerberg, Michael Lanuti, Motaz Qadan, Kenneth K. Tanabe. Inhibiting methionine aminopeptidase 2 prevents liver fibrosis and hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 108.