Résumé
Background: In spite of wide application of sorafenib for advanced 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 sub-populations of cancer cells named Cancer Stem Cells (CSCs) have been claimed as responsible of some tumor recurrences. Indeed, CSCs are resistant to chemotherapy, and they have the ability to regenerate all the tumor bulk with its heterogeneous cell type populations. For this reason, new drugs with original mechanism of action which target CSC properties would likely improve cancer treatment
Material and methods: Antitumor activity of GNS561 was tested on a panel of cancer cell lines and primary tumors. GNS561 impact on CSCs subpopulation in patient derived cells from colorectal hepatic metastatic tumors was assessed by flow cytometry (ALDH activity). In HCC, the effect of this drug was evaluated by sphere formation assay as readout to estimate CSC survival. Tolerance and plasma and liver pharmacokinetic were evaluated after single and repeated dosing in mice and rats. In vivo GNS561 activity was tested in orthotopic mouse model
Results: GNS561 demonstrated multiple cellular effects such as inhibition of autophagy, induction of apoptosis and cell cycle modulation. It showed antitumor activity against several human cancer cell lines. Furthermore, GNS561 was effective against a panel of HCC tumors even from patients harboring sorafenib resistance. GNS561 showed nonetheless an original dose-response cytotoxic activity against the whole tumor populations but also against a subpopulation displaying high ALDH activity in three CRC patient-derived cell lines established from fresh liver metastasis biopsies. Consequently, on the same model this compound induced a striking decrease of sphere formation. In HCC cell lines GNS561 was active on both whole populations (mean EC50 2µM) and subpopulations displaying CSC features (Epcam high). In addition, in the opposite of sorafenib, GNS561 decreases the HCC cell capacity to form spheroids. In mouse, GNS561 was found well tolerated and highly selectively trapped in the liver (exposure ratio liver/plasma about 170 animals). In HCC PDX mouse model, tumor growth was significantly reduced by GNS561 with a dose-response manner, this tumor regression was associated with AFP level decreases by 72% with GNS561 (p=0.002) and 54% with sorafenib (p=0.046) compared to control
Conclusions: GNS561 is a liver selective drug which offers great promise for HCC and liver metastatic tumors treatment. By simultaneously targeting the cancer stem cell subpopulation and tumor bulk, both cell heterogeneity, plasticity and recurrences could be overcome at least in colorectal cancer and HCC. GNS 561 is now aimed to further reach clinical development in patients in 2017
Note: This abstract was not presented at the meeting.
Citation Format: Firas Bassissi, Elena Patricia Gifu, Sonia Brun, Jerome Courcambeck, Antoine Beret, Jean Marc Pascussi, Julie Pannequin, Eric Raymond, Philippe Halfon, Philippe Merle, Claude Caron de Fromentel. GNS561 is a new quinoline derivative with high efficacy on cancer stem cells from colorectal liver metastasis and hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1914. doi:10.1158/1538-7445.AM2017-1914