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GNS561 a new quinoline derivative inhibits the growth of hepatocellular carcinoma in a cirrhotic rat & human PDX orthotopic mouse models

Firas Bassissi1, Zuzana Macek Jilkova2,3, Sonia Brun1, Jerome Courcambeck1, Jennifer Tracz1, Keerthi Kurma2,3, Gaël S Roth2,3,4 , Cindy Khaldi1, Corinne Chaimbault1, Benoit Quentin, Emilie Asseraf1, Antoine Beret1, Eric Raymond1, Philippe Halfon1 and Thomas Decaens2,3,4

Abstract:


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 561 was more efficient than sorafenib to control tumor growth in preclinical
models. Based on its safe toxicity profile and potent activity in rodent models, GNS 561 is now aimed
to further reach clinical development in patients with HCC in 2017.


Keywords:
Hepatocellular carcinoma (HCC), Resistance, Cancer, Liver cirrhotic rat


1‐ Genoscience Pharma, Marseille, France
2‐ Université Grenoble Alpes, France
3‐ Institute for Advanced Biosciences, Research Center UGA / Inserm U 1209 / CNRS 5309, Grenoble, France
4‐ Clinique Universitaire d’Hépato‐gastroentérologie, Pôle Digidune, CHU Grenoble, France