Abstract: The present invention relates to pharmaceutical compositions for use in the treatment of chemoresistant acute myeloid leukemia (AML). The inventors have established a powerful preclinical model to screen in vivo responses to conventional genotoxics and to mimic the chemoresistance and minimal residual disease as observed in AML patients after chemotherapy. The inventors showed that cytarabine-resistance mechanism involves the CD39-dependent crosstalk between energetic niche and AML mitochondrial functions through CD39-P2Y13-cAMP-PKA signaling axis. In particular, the present invention relates to an inhibitor of the CD39-P2Y13-cAMP-PKA signaling axis for use in a method of treating chemoresistant acute myeloid leukemia (AML) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of said inhibitor.

Abstract: After intensive chemotherapy, the emergence of cells with dmg resistant and/or stem cell features might explain frequent relapses and the poor outcome of patients with acute myeloid leukemia (AML). Herein the inventors first uncovered that the adrenomedullin receptor CALCRL is overexpressed in AML patients comparing with normal cells and preferentially in the immature CD34+ CD38? compartment. Then they demonstrated its role in the maintenance of leukemic stem cell function in vivo. Moreover, CALCRL depletion strongly affected leukemic growth in xenograft models and sensitized to chemotherapeutic agent cytarabine in vivo. It Accordingly, the inventors showed that ADM-CALCRL axis drove cell cycle, DNA integrity, and high OxPHOS status of chemoresistant AML stem cells in an E2F1- and BCL2-dependent manner. Furthermore, CALCRL depletion sensitizes cells to cytarabine and its CT expression predicted the response to chemotherapy in vivo in mice.

Abstract: The present invention relates to pharmaceutical compositions for use in the treatment of chemoresistant acute myeloid leukemia (AML). The inventors have established a powerful preclinical model to screen in vivo responses to conventional genotoxics and to mimic the chemoresistance and minimal residual disease as observed in AML patients after chemotherapy. The inventors showed that cytarabine-resistance mechanism involves the CD39-dependent crosstalk between energetic niche and AML mitochondrial functions through CD39-P2Y13-cAMP-PKA signaling axis. In particular, the present invention relates to an inhibitor of the CD39-P2Y13-cAMP-PKA signaling axis for use in a method of treating chemoresistant acute myeloid leukemia (AML) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of said inhibitor.

Abstract: Dendrogenin A and antineoplastic agents for the treatment of chemosensitive or chemoresistant tumors. The invention concerns a kit-of-parts comprising 5?-hydroxy-6?-[2-(1H-imidazol-4-yl)ethylamino]cholestan-3?-ol (Dendrogenin A) or a pharmaceutically acceptable salt thereof and an antineoplastic agent for use in the treatment of cancer. Furthermore, the invention concerns Dendrogenin A or a pharmaceutically acceptable salt thereof for use for treating a chemoresistant cancer.

Abstract: Dendrogenin A and antineoplastic agents for the treatment of chemosensitive or chemoresistant tumors. The invention concerns a kit-of-parts comprising 5?-hydroxy-6?-[2-(1H-imidazol-4-yl)ethylamino]cholestan-3?-ol (Dendrogenin A) or a pharmaceutically acceptable salt thereof and an antineoplastic agent for use in the treatment of cancer. Furthermore, the invention concerns Dendrogenin A or a pharmaceutically acceptable salt thereof for use for treating a chemoresistant cancer.