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.
Highlights
Acute myeloid leukemia (AML) is a leading cause of cancer-related death in young adults and represents 100 000 cases per year in G8 countries
Most remissions remain short-lived as 60–75% of adult patients ⩽ 60 years old and 85–95% of patients 460 years old still relapse and die from the disease,[6] most probably due to the outgrowth of leukemic stem cells (LSCs)
We predicted that the chemical interrogation of heterogeneous AML primary specimens for novel therapeutic targets would further increase this complexity
Summary
Acute myeloid leukemia (AML) is a leading cause of cancer-related death in young adults and represents 100 000 cases per year in G8 countries. It is well accepted that AML represents several distinct entities, with high genetic complexity, not always accurately defined by standard cytogenetic methods Given this complexity, we predicted that the chemical interrogation of heterogeneous AML primary specimens for novel therapeutic targets would further increase this complexity. We looked for biostatistical methods, which help associate chemical activities to molecular features of assessed biological samples Such methods, relying on compound clustering, have been previously reported in yeast, fungus and cancer cell lines but never with primary specimens.[26,27,28]. In all maximum of CCC therapeutic classes (see Supplementary Figure 1) and exclusion of hypersensitive specimens (defined by displaying percentages of inhibition in the primary screen 495% for at least three of the five compounds studied).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
