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Blood Cancer J. 2017 Feb 17;7(2):e529. doi: 10.1038/bcj.2017.10.

A novel approach for the identification of efficient combination therapies in primary human acute myeloid leukemia specimens.

Author information

1
The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada.
2
Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada.
3
Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada.
4
Faculty of Medicine, Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
5
Department of Computer Science and Operations Research, Université de Montréal, Montréal, Québec, Canada.
6
Department of Chemistry, Université de Montréal, Montréal, Québec, Canada.

Abstract

Appropriate culture methods for the interrogation of primary leukemic samples were hitherto lacking and current assays for compound screening are not adapted for large-scale investigation of synergistic combinations. In this study, we report a novel approach that efficiently distills synthetic lethal interactions between small molecules active on primary human acute myeloid leukemia (AML) specimens. In single-dose experiments and under culture conditions preserving leukemia stem cell activity, our strategy considerably reduces the number of tests needed for the identification of promising compound combinations. Initially conducted with a selected library of 5000 small molecules and 20 primary AML specimens, it reveals 5 broad classes of sensitized therapeutic target pathways along with their synergistic patient-specific fingerprints. This novel method opens new avenues for the development of AML personalized therapeutics and may be generalized to other tumor types, for which in vitro cancer stem cell cultures have been developed.

PMID:
28211886
PMCID:
PMC5386329
DOI:
10.1038/bcj.2017.10
[Indexed for MEDLINE]
Free PMC Article

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