RSS

 

Genocience Pharma Will Present Data on Product Candidates Targeting Cancer Stem Cells at the 26th EORTC-NCI-AACR SYMPOSIUM Barcelona, Spain, 18-21 November 2014

Poster n°138 :  GNS396 and analogues are potent new small molecules to target and kill chemotherapy‐resistant subpopulation cells in acute myeloid leukemia

Firas Bassissi, Rémy Castellano, Emmanuelle Josselin, Camille Motersino, Laurent Pouyet, Armelle Goubard, Audrey Restouin, Gregory Nicolas, Sonia Brun, Jerome Courcambeck, Clarisse Dubray, Thomas Prébet, Norbert Vey, Antoine Beret, Philippe Halfon and Yves Collette

Abstract:

Despite efforts to understanding and treat acute myeloid leukemia (AML), there remains a need to more comprehensive therapies to prevent AML relapses and to reach sustainable clinical responses. To explain this phenomenon, the cancer stem cells/Leukemia initiating cells (CSCs/LICs) hypothesis suggests that tumors contain a small number of tumor-initiating cells, self-renewing cancer stem cells. Unlike most cells within the tumor, CSCs/LICs are resistant to chemotherapy, and after treatment, they can regenerate all the cell type in the tumor through their stem cell-like behavior. For this reason, innovative drugs which could tackle CSCs/LICs improve cancer treatment of patients.
We screened a library of autophagy inhibitor compounds and identified new drugs GNS396 and analogues as compound that kills AML cells and LSCs in a panel of leukemia cell lines and primary tumor. The effect of GNS396 and analogues on LICs population was measured using ALDH activity marker, as evaluated by their AldefluorTM dehydrogenase activity by flow cytometry. A synergy study combining the cytarabine with the GNS 396 was performed on MOLM-14 14 cell Line. In vivo tumor growth was evaluated in an orthotopic NSG-mice AML model of transplanted human MOLM-14 cell line displaying Cytarabine resistance (unpublished data).
GNS396 demonstrates autophagy inhibition and apoptosis induction activities which are probably related to lysosome disruption. GNS 396 shows potent anti-proliferation activity when assayed against the NCI60 panel of human tumor cell lines, notably against AML cell lines (Mean GI50 6μM), as well as an original dose-responses cytotoxic activity against AML cell lines subpopulation displaying high ALDH activity. Furthermore GNS396 shows a synergic effect in combination with Cytarabine on MOLM-14 cell viability. In vivo GNS396 that is well tolerated by mice induces significant reduction of leukemia growth by about 60% in MOLM14 xenografted mice.
Our results provide a rationale for testing lysosome disruption as a novel therapeutic strategy for AML. GNS396 and analogues offer great promise for AML treatment and prevention of relapse in AML patients in particular in combination with chemotherapy. By simultaneously targeting the tumorigenic (by GNS396) and non-tumorigenic populations (by both GNS396 and Cytarabine), both leukemia cell heterogeneity and plasticity could be overcome. This compound is selected as a drug candidate for future investigation in AML clinical trial.

Keywords:
Cancer stem cells (CSCs), Leukemia initiating cells (LICs), Acute Myeloid Leukemia (AML), resistance,
Cancer