Abstract
Background: Patients with advanced hepatocellular carcinoma (HCC) or advanced colorectal cancer (CRCm) have a poor prognosis due to lack of effective treatments. As observed in several types of tumors, the effectiveness of treatments is hampered by the presence of a highly tumorigenic sub-population of cancer cells called cancer stem cells (CSC) CSC are resistant to chemotherapy and radiotherapy and have the ability to regenerate tumor mass. Therefore, innovative drugs that are effective against tumor cells as well as CSC would likely improve cancer treatment. Here, we studied the activity of GNS561, a new autophagy inhibitor targeting the palmitoyl-protein thioesterase 1 (PPT-1), against CSC in HCC and liver metastases of colorectal cancer. Methods: Viability and aldehyde dehydrogenase (ALDH, a cancer CSC marker) were studied on Hep3B and Huh7 cell lines; and cell lines derived from liver mCRC patients (CPP19, 30, 36 and 45) treated with GNS561 or diluent as a control In vitro tumorspheres formations have been performed and in some experiments CSC subpopulations of HCC cell lines have been isolated and quantified. Results: In this study, we demonstrated that GNS56, a new PPT-1 inhibitor inducing autophagy, causes cell death and shows significant activity not only against the entire tumor population, but also a subpopulation with CSC characteristics (high ALDH activity and tumorspheres formation capacity) in the liver HCC and mCRC. These results were confirmed in vivo in HCC from a DEN-induced rat cirrhotic model in which GNS561 reduced tumor growth and CSC frequency (CD90 +CD45 -) Conclusion: In conclusion, GNS561, which has just completed an international phase 1b clinical trial in HCC, is a very promising compound for the treatment of cancer by targeting the tumor mass and CSC subpopulation