Studying cytarabine resistance through PDX models in acute myeloid leukemia

Thomas Farge1,2,5, Nesrine Aroua1,2,5, Fabienne de Toni1,2,5, Virginie Feliu1,2,5, Robin Perry3, François Vergez1,2,5, Estelle Saland1,2,5, Marie-Laure Travers1,2,4,5, Suzanne Tavitian4,5, Olivier Duchamp5,6, Gwenn Danet-Desnoyers3, Martin Carroll3, Christian Récher1,2,4,5 and Jean-Emmanuel Sarry1,2,5

1INSERM, Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France; 2University of Toulouse, F-31300 Toulouse, France; 3Division of Hematology & Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; 4Département d’Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, F-31059 Toulouse, France; 5 Consortium IMODI; 6 Oncodesign, 21000 Dijon

The major therapeutic barrier in acute myeloid leukemia (AML) is chemotherapy resistance.AML cells resistant to conventional chemotherapy targeting DNA synthesis are thought to beenriched in quiescent leukemic stem cells (LSCs). In order to better understand chemotherapyresistance in AML, we analyzed the response to cytarabine (AraC) through patient-derivedxenograft (PDX) models with 20 primary AML patient specimens from two clinical sites and inthe context of a French “Innovative models initiative” (IMODI) program.

Introduction

Results

Materials and Methods ConclusionPeripheral blood cells from 20 AML patient were injected in NSG mice (n=15-20/patients).Engraftment was monitored by flow cytometry in mice peripheral blood. When the AML isestablished, mice were treated with AraC administered IP for 5 days as a single agent at 60mg/kg daily. In vivo AraC response in PDX models has been compared to clinicobiological dataof their matched patients. Finally, residual leukemic cells (RLCs), surviving after in vivo AraCtreatment, have been characterized for their cell surface phenotype, stem cell frequency, cellcycle and metabolic status.

Altogether, these results suggest a novel model of AraC chemotherapy resistance uncoveringthe control of the oxidative and mitochondrial energy metabolism in vivo and the relevance ofPDX models for clinical investigations and new preclinical drug assessment. Further studies ofthe role of immune and stromal microenvironment will be assessed in this model to extend ourfindings in a more relevant setting

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Fig3 In vivo response to cytarabine (AraC) in PDX: Signature phenotype, cell cycle and red/ox status of residual leukemic cells

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Utilization of cytarabine in patient derived xenograft models of acute myeloid leukemia