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

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.

[The prognostic tools of hepatitis C virus infections]. / Les outils du pronostic de l'infection par le virus de l'hépatite C.

INCREASE IN ALANINE AMINOTRANSFERASE (ALAT): Used for many Years in the diagnosis and follow-up of chronic hepatic diseases related to HCV, the determination of ALAT presents various limits: variation from one patient to the other and in the same patient over time, absence of specificity and inconstant increase. HISTOLOGICAL ASSESSMENT OF THE INVOLVEMENT OF THE LIVER: The hepatic needle-biopsy remains the best means of assessing precisely the hepatic impact. Several scores of hepatic involvement exist, the most frequently used is the Metavir score that takes into account not only the necrotic-inflammatory activity but also the fibrosis. OTHER THAN THE HEPATIC NEEDLE-BIOPSY: There are complications with the hepatic needle-biopsy and non-invasive markers of fibrosis and hepatic necrotic-inflammatory activity have been looked for. Two scores have hence been developed from the measurement in the blood of 4 proteins (apolipoprotein A1, alpha2 macroglobulin, haptoglobin and bilirubin) and 2 enzymes (alanine aminotransferase and gamma-glutamyl transpeptidase) which provide an acurate assessment of the fibrosis (Fibrotest) and the necrotic-inflammatory activity (Actitest).