MITHAML – Exploring the role of Metabolic IntraTumoral Heterogeneity in drug resistance of Acute Myeloid Leukemia in vivo

Drug resistance is a major barrier in acute myeloid leukemia (AML) for which prognosis remains unfavorable.

We and others have shown the importance of metabolism in the response to therapies in AML, leading to the development of several drugs targeting mitochondrial functions such as BCL2 inhibitor Venetoclax or Electron Transfer Chain Complex I inhibitor IACS-010759.

Tumors are composed of genetically and phenotypically heterogeneous cell populations, not all cells being equal in their ability to respond to treatment.

Tremendous advances in single-cell technologies like mass cytometry (CyTOF) have demonstrated a fantastic potential to decipher this phenotypic and signaling heterogeneity.

However, metabolic features are mostly measured in bulk, impeding the assessment of the metabolic cellular heterogeneity.

We propose to investigate the role of metabolic intratumoral heterogeneity in AML at diagnosis and after new drugs in vivo through 2 aims.

First we will determine the relationship between metabolic, signaling and developmental states in healthy and leukemic myeloid bone marrow cells and its link with chemoresistance (Aim 1).

Then we will focus on the impact of Venetoclax and IACS on MITH in vivo using patient-derived xenograft mice models to identify specific features related to resistance to these drugs that we will finally therapeutically target with new combinations in vivo (Aim 2).

The skills of the experienced researcher (ER) on metabolism and omic technologies and the complementary expertise of the 2 laboratories are key for the success of MITHAML.

Indeed, the ER will be trained for 2-years in Dr Davis’s lab (Stanford University, USA), highly recognized in the study of intratumoral heterogeneity especially with CyTOF. She will then bring back these skills in Dr Sarry’s lab (Inserm, France), expert in in vivo AML resistance.

This fellowship will be key to help the ER develop the scientific, technological and management skills required for her independence.