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GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma

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Summary

Among the acquired modifications in cancer cells, changes in lysosomal phenotype and functions are well described, making lysosomes a potential target for novel therapies. Some weak base lipophilic drugs have a particular affinity towards lysosomes, taking benefits from lysosomal trapping to exert anticancer activity. Here, we have developed a new lysosomotropic small molecule, GNS561, and assessed its activity in multiple in vitro intrahepatic cholangiocarcinoma models (HuCCT1 and RBE cell lines and patient-derived cells) and in a chicken chorioallantoic membrane xenograft model. GNS561 significantly reduced cell viability in two intrahepatic cholangiocarcinoma cell lines (IC50 of 1.5 ± 0.2 μM in HuCCT1 and IC50 of 1.7 ± 0.1 μM in RBE cells) and induced apoptosis as measured by caspases activation. We confirmed that GNS561-mediated cell death was related to its lysosomotropic properties. GNS561 induced lysosomal dysregulation as proven by inhibition of late-stage autophagy and induction of a dose-dependent build-up of enlarged lysosomes. In patient-derived cells, GNS561 was more potent than cisplatin and gemcitabine in 2/5 and 1/5 of the patient-derived cells models, respectively. Moreover, in these models, GNS561 was potent in models with low sensitivity to gemcitabine. GNS561 was also efficient in vivo against a human intrahepatic cholangiocarcinoma cell line in a chicken chorioallantoic membrane xenograft model, with a good tolerance at doses high enough to induce an antitumor effect in this model. In summary, GNS561 is a new lysosomotropic agent, with an anticancer activity against intrahepatic cholangiocarcinoma. Further investigations are currently ongoing to fully elucidate its mechanism of action.

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Acknowledgements

The authors are very grateful to Dr. Emilien Dosda, Dr. Xavier Rousset and Sylvain Roveda from Inovotion for their work on the CAM study.

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This study was supported by private funding.

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Authors and Affiliations

  1. Genoscience Pharma, 10 Rue d’Iéna, Marseille, France

    Sonia Brun, Firas Bassissi, Cindy Serdjebi, Marie Novello, Jennifer Tracz, Jérôme Courcambeck, Christelle Ansaldi, Eric Raymond & Philipe Halfon

  2. Biomarker Discovery Department, Evotec SAS, 195 Route d’Espagne – BP13669, Toulouse, France

    François Autelitano, Marie Guillemot & Philippe Fabre

  3. Department of Oncology, Hôpital Paris Saint Joseph, 185 Rue Raymond Losserand, Paris, France

    Eric Raymond

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Brun, S., Bassissi, F., Serdjebi, C. et al. GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma. Invest New Drugs 37, 1135–1145 (2019). https://doi.org/10.1007/s10637-019-00741-3

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  • DOI: https://doi.org/10.1007/s10637-019-00741-3

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