Abstract B06: Studying cytarabine resistance through PDX models in acute myeloid leukemia

Abstract

Abstract The major therapeutic barrier in acute myeloid leukemia (AML) is chemotherapy resistance. AML cells resistant to conventional chemotherapy targeting DNA synthesis are thought to be enriched in quiescent leukemic stem cells (LSCs). In order to better understand chemotherapy resistance in AML, we analyzed the response to cytarabine (AraC) through patient-derived xenograft (PDX) models with 20 primary AML patient specimens from two clinical sites and in the context of a French “Innovative models initiative” (IMODI) program. After confirming AML engraftment, highly immunodeficient NOD/LtSz-scid IL2Rγc null (NSG) mice were treated with AraC administered IP for 5 days as a single agent at 60 mg/kg daily, which correlates with human dosing. In all mice treated with this regimen, there was a significant but variable cytoreductive effect (4- to 46-fold reduction of tumor cell burden; 2- to 13-fold induction of apoptosis) at 3 days post-treatment. This in vivo AraC response in PDX models has been compared to clinicobiological data of their matched patients (including overall survival, FAB classification, and age at diagnosis). Furthermore, residual leukemic cells (RLCs), surviving after in vivo AraC treatment, have been characterized for their cell surface phenotype, stem cell frequency, cell cycle and metabolic status. Gene expression of RLCs from three different PDX models showed an enrichment of genes involved in inflammatory, immune and stress/ROS responses. When tested in three independent cohorts of AML patients (Verhaak et al. 2009; TGCA. 2011; Metzeler et al. 2011), the down-regulated gene signature is associated with an unfavorable prognosis in patients treated with intensive chemotherapy. Altogether, these results suggest a novel model of AraC chemotherapy resistance uncovering the control of the oxidative and mitochondrial energy metabolism in vivo and the relevance of PDX models for clinical investigations and new preclinical drug assessment. Further studies of the role of immune and stromal microenvironment will be assessed in this model to extend our findings in a more relevant setting. Citation Format: Thomas Farge{Authors}. Studying cytarabine resistance through PDX models in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B06.