Imeglimin Alone Or In Combination With Sorafenib Showed Potent Anti-Tumor Effect In Human Hepatocellular Carcinoma: A New Kid On The Block For Hcc Treatment

Background: Diabetes as a standalone or as part of metabolic syndrome is recognized as a major risk factor in hepatocellular carcinoma (HCC). Metformin one of the most widely used first-line drug for the treatment of type II diabetes showed antitumor activity in preclinical models of HCC, and in some clinical trials. Imeglimin, a first-in-class tetrahydrotriazine oral antidiabetic agents, is currently in phase III clinical trial in diabetes with a good safety profile. Imeglimin stands as an AMPK activator and based on historical data with metformin may be a safe potentially interesting novel therapeutic drugs for patients with HCC. Hence, the current study aims to evaluate the effects of imeglimin alone or in combination with sorafenib compared to metformin in an experimental model of HCC. Methods: All in vivo experiments were carried out with ethical committee approval and met the standards required by the UKCCCR guidelines. HepG2 HCC cells were injected subcutaneously (2 × 106cells) into the flank of female athymic nude mice. Two weeks after cell inoculation, 90% mice developed single subcutaneous palpable tumors. Mice were randomized in the groups of treatment. Mice were then treated 5 days a week by oral gavage with 75 mg/kg/day metformin (n=14-metformin75), 75 mg/kg/day imeglimin (n=14-Imeglimin75), 150 mg/kg/day imeglimin (n=14-Imeglimin150), 40 mg/kg/day sorafenib (n=14), metformin75 plus sorafenib (n=14) or imeglimin75 plus sorafenib (n=14). Body weight and tumor volumes were assessed thrice a week. Mice were sacrificed after 63 days of treatment to meet ethical requirements (tumor volume Results: Our experiments showed a 90% uptake in the engrafted mice. Regardless of the administrated treatment, no toxicity was observed as shown by the body weight follow-up. After 63 days of treatment, each treatment arm showed a slight difference with placebo (n=14). Mean tumor volumes were 1096±208 mm3 (P\u003e0.05), 795±222 mm3 (P\u003e0.05), 563±135 mm3 (P Conclusion: This study showed the antitumor effects of imeglimin, a novel AMPK activator in human HCC. Furthermore, imeglimin potentiates the antitumor effects of sorafenib, which may represent an interesting therapeutic option for patients with HCC. Citation Format: Annemilai Tijeras-Raballand, Matthieu Martinet, Valerie Paradis, Jean-Pierre Bizzari, Eric Janin, Eric Raymond. Imeglimin alone or in combination with sorafenib showed potent anti-tumor effect in human hepatocellular carcinoma: A new kid on the block for HCC treatment [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 5312.