Abstract 5124: GNS561 a new quinoline derivative inhibits the growth of hepatocellular carcinoma in a cirrhotic rat and human PDX orthotopic mouse models

Background: Hepatocellular carcinoma (HCC) remains a major health problem, often diagnosed at late stages with limited number of therapeutic options. New drugs with original mechanisms of action are urgently aimed to improve current armamentarium in HCC patients. Quinoline derivatives are novel class of oral small molecules inducing multiple cellular effects such as inhibition of autophagy, induction of apoptosis, and cell cycle modulation. The aim of these studies was to assess tolerance and efficacy of a new quinolone derivative GNS561. Material and methods: In vitro experiments were realized with viability, apoptosis and migration in tumor cells in HCC cell lines and primary tumor. Drug tolerance and plasma and liver pharmacokinetic were evaluated after single and repeated dosing in mice and rat. GNS561 and sorafenib efficacy in vivo were evaluated in a PDX orthotopic BALB/c-nu mouse model and in a diethylnitrosamine (DEN)-induced HCC cirrhotic rat model. AFP, cell proliferation and tumor weight and size were assessed in mice. In rat tumor progression was followed by MRI, pathological analysis (tumor size and number), immunohistochemistry and PCR analysis after 6weeks of treatment. Results: GNS 561 shows potent anti-proliferative activity when assayed against a panel of human tumor cell lines and notably against a panel of HCC patient primry tumors even in those with sorafenib resistance (Mean EC50 3µM vs 11µM for sorafenib). GNS561 is highly selectively trapped in the liver. Plasma and liver PK in mice and rats after single and repeated doses confirm this selectivity with good tolerance and oral bioavailability. In PDX mouse model, tumor growth was significantly reduced by GNS561 with a dose-response manner, this tumor regression was associated with AFP level decreases by 72% with GNS561 (p=0.002) and 54% with sorafenib (p=0.046) compared to control. In rat model, mean number of tumors was significantly lower in GNS561 at 15mg/kg group (n=50.6), in sorafanib at 10mg/kg (n=65.1) and in combination group (n=40.6), when compared to control (n=100.4; p=0.0024, p= 0.029 and p=0.0002). Tumor decrease measured by MRI was associated with a significantly reduced proliferation of tumor cells particularly in GNS561 group (70%) and combination (84%) compared to control, whereas the effect of sorafenib alone on proliferation was modest (30%). Conclusions: GNS561 is a liver selective drug with good tolerance and promising efficacy in different HCC animal models. GNS