Objective
"Clonal evolution represents a driving force for cancer cells and a major challenge for therapy. There is a long-standing knowledge that clonal diversification and selection allows cancer cells to pass through distinct steps of transformation. More recently has emerged the concept that ""more malignant"" leukemia subclones can persist after treatment leading to relapse. My research is focused on two diseases which represent privileged models to study clonal evolution: Fanconi anemia (FA), which is a genetic condition predisposing to acute leukemia, and T-cell acute lymphoblastic leukemia (T-ALL), an aggressive leukemia which frequently relapses. The goal of this project is to decipher the crucial molecular and cellular events that drive gain of malignancy and to design new strategies to follow up and treat the patients. Specifically, we aim to:
1. Identify the key pathways involved in leukemia progression at two major steps: from pre-leukemia to overt leukemia (in FA), and from primary diagnosis to relapse (in T-ALL). This aim will use high-throughput molecular profiling and functional characterization of longitudinal samples from patients.
2. Model leukemia progression in vivo to functionally validate these pathways. We have developed read-outs based on gene silencing in human primary cells from patients followed by leukemia monitoring in immunodeficient mice.
3. Define new strategies to prevent the transition towards acute leukemia in pre-leukemic states in FA patients. We will develop new markers for transformation that should help in monitoring therapeutic intervention.
4. Test drugs in pre-clinical models to target critical pathways of relapsed ALL. We will use xenografted T-ALL which recapitulates leukemia progression.
Completion of this innovative transversal project should markedly improve the knowledge on tumor progression and lead to new strategies to prevent, early detect and/or treat relapse, with the final objective to cure more patients."
Fields of science
Call for proposal
ERC-2012-StG_20111109
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Funding Scheme
ERC-SG - ERC Starting GrantHost institution
F-75205 / 13 Paris
France