The project aims to define a functional description of transcriptional and metabolic rewiring of transient and persistent therapy resistant and leukemia initiating cells, and identify novel therapeutic strategies based on evolutionary traps for AML MRD.
There is an urgent need to identify biomarkers of resistance to azacitidine/venetoclax (AZA/VEN), the first line treatment for unfit AML patients. The researcher will search for multiomic pathways including metabolomic dependencies associated with MRD in AML patients treated with AZA/VEN treatment. Existing methods allowing single-cell whole transcriptome analysis, transcript mutation annotation, intracellular epitope detection harbored by anti-apoptotic and metabolic proteins that are critical and rate-limiting in their representative pathways will be leveraged.
The researcher will characterize the multiomic adaptation of leukemic cells in the first days of AZA/VEN treatment and in MRD banked samples from the DREAM clinical trial (NCT06225128). Moreover, AZA/VEN resistance will be studied in AML PDX models and a mouse Tet2-/- syngeneic model.
Finally, drugs directed to the identified metabolic/transcriptomic characteristics using the evolutionary trap approach will be validated using a niche-dependent AML culturing system developed by us, followed by in vivo validation in the Tet2-/- syngeneic model.
Host:
INSERM, Paris, France
Supervisors:
Dr. Alexandre Puissant and Prof. Raphael Itzykson