RSS

 

GNS561 is a new quinoline derivative with high efficacy on cancer stem cells from colorectal liver metastasis and hepatocellular carcinoma

S. Brun1, E.P. Gifu2, Z. Macek-Jilkova4, J. Courcambeck1, J.M. Pascussi3, J. Pannequin3, E. Raymond1, F. Bassissi1, P. Halfon1, P. Merle2, T. Decaens4,5 and C. Caron de Fromentel2

Background: In spite of wide application of sorafenib for hepatocellular carcinoma (HCC) treatment, and systemic chemotherapy cocktails (5-fluorouracil, irinotecan, and oxaliplatin) for metastatic colorectal cancer, the prognostic for both cancers remains poor. In recent years, highly tumorigenic subpopulation of cancer cells named cancer stem cells (CSC) has been claimed as responsible of some tumor recurrences. Indeed, CSC are resistant to chemotherapy and have the ability to regenerate ad infinitum all the tumor bulk with its heterogeneous cell type populations. For this reason, innovative drugs which target CSC properties would likely improve cancer treatment of patients. GNS561 is a small molecule able to induce an apoptotic cell death associated with triggering among others an activation of caspases 3/7 and an inhibition of lysosomal enzymes. Previous work has been shown that the molecule has strong hepatotropism which justifies its potential usage against hepatocellular carcinoma and liver metastatic tumors.


Material and methods: Anti-tumor activity of GNS561 was tested on some cancer cell lines and primary tumors. GNS561 impact on CSC subpopulation was assessed by flow cytometry (ALDH high or CD90+CD45-) and by sphere formation assay. In vivo, GNS561 activity was tested in a cirrhotic rat model. MRI analysis was performed to follow the tumor progression.


Results: GNS561 showed potent anti-tumor activity in a panel of human cancer cell lines and in HCC patient-derived cells even from patients harboring sorafenib resistance. Moreover, in three patient-derived cells from colorectal hepatic metastatic tumors, GNS561 showed nonetheless a dose‐response activity against the whole tumor population but also against a subpopulation displaying CSC features (high ALDH activity). In this model, GNS561 induced a striking decrease of sphere formation. Similarly, in HCC cell lines, GNS561 was active on both populations (bulk and CSC) and decreased the cell capacity to form spheroids (in the opposite of sorafenib). In vivo, in induced HCC cirrhotic rat model, after 36 days oral treatment, GNS561 showed anti-tumor effects with better efficacy than sorafenib and reduction of frequency of CSC (CD90+CD45-).


Conclusion: GNS561 is a liver selective drug which offers great promise not only for HCC treatment but also for liver metastatic tumors by simultaneously targeting the CSC subpopulation and tumor bulk. GNS561 is now aimed to further reach clinical development in patients in June 2017.

1 Genoscience Pharma, Marseille, France;

2 CRCL, INSERM U1052 / CNRS 5286, Université Lyon1 ‐ Centre Léon Bérard, Lyon, France;

3 IGF, Montpellier, France;

4 Institute for Advanced Biosciences, Research Center UGA / INSERM U1209 / CNRS 5309, La Tronche, France;

5 Clinique Universitaire d’Hépato‐gastroentérologie, Grenoble, France