Despite a high rate of complete remission after treatment with genotoxic agents, the prognosis is very poor in human acute myeloid leukemia (AML).
Indeed, 5-year overall survival is about 30 to 40% in patients younger than 60 years old and less than 20% in patients over 60 years. Front-line chemotherapy based on a combination of an anthracycline (eg. daunorubicin, DNR, or idarubicin, IDA) and a nucleoside analogue (eg. cytarabine, AraC) is highly effective in ablating leukemic cells, but distant relapses are observed in the majority of patients, characterized by a refractory phase during which no other treatment has shown any efficacy thus far (Tallman et al. 2005; Burnett et al. 2011). Relapses are caused by tumor regrowth initiated by resistant leukemic clones (RLCs). The biology of therapeutic resistance currently represents an active area of research. However, the molecular mechanisms underlying AML chemoresistance are still poorly understood, especially in the in vivo context.
The goal of our Team is to understand the causes of drug resistance for the development of new treatments eradicating RLCs and overcoming patient relapses. Our hypothesis is that RLCs have specific mitochondrial energetic and metabolic features mediated by metabolic interactions with stromal cells, which modulates their therapeutic resistance in the tumoral niche. For that, using diverse metabolomic, transcriptomic, pharmacological and functional approaches as well as patient samples and a newly developed AML-engrafted immunodeficient models (Sarry et al. 2011, Farge et al. 2017), we propose to 1/ elucidate the stemness and functional heterogeneity of RLCs in response to genotoxics in vivo, and to 2/ determine how reprogrammed mitochondrial energy and metabolic signaling networks drive the drug resistance of RLCs in vivo. Jean-Emmanuel Sarry’s team is part of Oncodevice, IMODI, Labex TOUCAN & PHUC CAPTOR.
As of today, 436 people represent the research strengths of the CRCT. Among these people, we find more than 50 permanent researchers from the Inserm, CNRS and the Claudius Regaud Institute, 60 professors and assistant-professors from the University of Toulouse III, about 20 clinicians from the IUCT-O, about 30 post-doctoral fellows and more than 60 PhD students. The very strong scientific dynamism of CRC is particularly well illustrated by a scientific structuration around 3 scientific axes and 2 integrated scientific programs. The scientific axes are : ‘Oncogenic signaling, DNA damage response and genetic instability’, ‘RNA-biology processing, epigenetics and gene expression’, ‘Microenvironment and onco-immunology’. The integrated CRCT/IUCT-O scientific programs are : ‘Mechanism of resistance and new targets : from molecular to clinical pharmacology’, ‘Development of mathematics, physics and computational tools in oncology’, in collaboration with local partners from the Toulouse Institute of Mathematics (IMT), from the Toulouse Research Institute of Informatics (IRIT) and from the Laboratory for Analysis and Architecture of Systems (LAAS-CNRS). Finally, thanks to the excellence of its production and its scientific dynamism, the CRCT, which already benefits from a broad network through its researchers, is involved in structural partnerships with regional (IRCM Montpellier), national CRCL Lyon) and international (Technion Tel-Aviv, DKFZ Heidelberg) research centers.