J Cancer 2021; 12(18):5432-5438. doi:10.7150/jca.58533

Research Paper

GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer

Sonia Brun1,✉, Jean-Marc Pascussi2,#, Elena Patricia Gifu3,#, Eloïne Bestion1,4 #, Zuzana Macek-Jilkova5,6,7, Guanxiong Wang3, Firas Bassissi1, Soraya Mezouar1, Jérôme Courcambeck1, Philippe Merle3,8, Thomas Decaens5,6,7, Julie Pannequin2, Philippe Halfon1,#,✉, Claude Caron de Fromentel3,#,✉

1. Genoscience Pharma, Marseille, France
2. IGF, University of Montpellier, CNRS, INSERM, Montpellier, France
3. CRCL, INSERM U1052, CNRS 5286, Université Lyon 1 ‐ Centre Léon Bérard, Lyon, France
4. Aix-Marseille Univ, MEPHI, APHM, IRD, IHU Méditerranée Infection, Marseille, France
5. Institute for Advanced Biosciences, Research Center UGA, Inserm U 1209, CNRS 5309, La Tronche, France
6. University of Grenoble Alpes, Faculté de Médecine, France
7. Clinique Universitaire d'Hépato‐gastroentérologie, Pôle Digidune, CHU Grenoble, France
8. Hepatology and Gastroenterology Unit, Croix-Rousse Hospital, Hospices Civils de Lyon, France
#These authors contributed equally

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Citation:
Brun S, Pascussi JM, Gifu EP, Bestion E, Macek-Jilkova Z, Wang G, Bassissi F, Mezouar S, Courcambeck J, Merle P, Decaens T, Pannequin J, Halfon P, Caron de Fromentel C. GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer. J Cancer 2021; 12(18):5432-5438. doi:10.7150/jca.58533. Available from https://www.jcancer.org/v12p5432.htm

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Abstract

Patients with advanced hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) have a very poor prognosis due to the lack of efficient treatments. As observed in several other tumors, the effectiveness of treatments is mainly hampered by the presence of a highly tumorigenic sub-population of cancer cells called cancer stem cells (CSCs). Indeed, CSCs are resistant to chemotherapy and radiotherapy and can regenerate the tumor bulk. Hence, innovative drugs that are efficient against both bulk tumor cells and CSCs would likely improve cancer treatment. In this study, we demonstrated that GNS561, a new autophagy inhibitor that induces lysosomal cell death, showed significant activity against not only the whole tumor population but also a sub-population displaying CSC features (high ALDH activity and tumorsphere formation ability) in HCC and in liver mCRC cell lines. These results were confirmed in vivo in HCC from a DEN-induced cirrhotic rat model in which GNS561 decreased tumor growth and reduced the frequency of CSCs (CD90+CD45-). Thus, GNS561 offers great promise for cancer therapy by exterminating both the tumor bulk and the CSC sub-population. Accordingly, a global phase 1b clinical trial in liver cancers was recently completed.

Keywords: GNS561, cancer stem cell, liver cancer, colorectal cancer, lysosome, therapy