PRECLINICAL MOUSE MODELS FOR NEW MOLECULES SCREENING IN THE TREATMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA B
- Preclinical development
- ALL
- Targeted therapy
- Chemotherapy
- Preclinical research (TRL 4-5)
Use of transgenic mouse models to develop pharmacological approaches by screening chemical compounds on B-ALL initiating and/or propagating cells.
The originality and competitive advantages of the offer are based on:
-
- The use of a chemical screening model on primary murine cells enriched with pre-leukemic ALL-B stem cells
- Evaluation of chemical compounds on cells carrying only a primary oncogene (initiator cells)
- Multiparametric FACS reading taking into account phenotypic heterogeneity of normal and pre-leukemic B-systems
- Simultaneous evaluation of the impact of each molecule on pre-leukemic cells and on all subpopulations of the normal B compartment (from pre-pro-B to mature B)
- Consideration of the dependence of normal and pre-leukemic B cells on their microenvironment (miniaturized co-culture on stromal cells)
- Chemical screening also possible on transformed leukemia cells (propagating cells carrying the primary oncogene and secondary genetic alterations)
Description
Scope of research activities
Preclinical research using a transgenic mouse model to screen drug candidates on pre-leukemic B-ALL stem cells.
- Murine model expressing the primary oncogene PAX5-ELN and recapitulating the multi-step development of B-ALL by acquisition of secondary events (Jamrog et al., 2018)
- Initiating pre-leukemic cells (PAX5-ELN oncogene) mimicking the molecular mechanisms of disease relapse in patients (Fregona et al., 2024)
- Transformed leukemia cells carrying secondary mutations
- Screening of drug candidates
Conducting studies
Steps :
- Analysis/definition of study strategy
- Identification of relevant compound libraries to be screened according to the question posed, including commercial libraries, custom libraries and academic libraries (Chimiothèque Nationale)
- Screening of candidate compounds on murine pre-leukemic (initiator) or leukemic (propagator) cells
- Selection of candidate compounds capable of inhibiting the viability of (pre-)leukemic cells and/or restoring their differentiation
- Dose-response counter-screening to determine IC50s of candidate molecules
- Collaboration with chemists to generate pharmacological analogues
- Synthesis and evaluation of biological activity of analogues
- Development and detailed investigation (in vitro and in vivo) of the selected analog
- Molecule testing on other mouse models of ALL-B (PAX5-P80R, TCF3-PBX1) and on PDXs (read more)
- Analysis and communication of results
Research infrastructure
Experimental and analysis platforms:
- Animal house
- Cell sorting platform
- Analytical cytometer
- Commercialized or contract chemical libraries
- CNRS French national chemical library (Mahuteau-Betzer, 2015)
Models :
- Murine models of ALL-B
Technical personnel:
- Engineer for screening and analysis
Specifications
The platform
Set of in vitro and in vivo preclinical models specific to B-ALL for the identification of drug candidates.
The studies
Primary screening of drug candidates:
- Day 0: Inoculation of MS5 stromal cells in 96-well plates
- Day 1: Enrichment and seeding of (pre-)leukemia cells from mice transgenic on stromal cells
- Day 1: Treatment (dose to be determined) of (pre-)leukemic cells (1 compound per well)
- Day 3: Multiparametric FACS analysis (12 antibodies) covering all B differentiation steps (from pre-pro-B to mature-B) and discriminating (pre-)leukemic cells (Fregona et al., 2024)
- Read out: Calculation of the percentage and absolute number of each normal and (pre-)leukemic B subpopulation
- Impact of each compound on normal and (pre-)leukemic B subpopulation cells.
Counter-screening of drug candidates:
- Dose-response counter-screening of selected hits (96-well plate, triplicate/dose)
- Calculation of IC50 for each selected hit
- Read out: Same as primary screening for each dose
Functional validation of drug candidate:
- In vitro treatment and transplantation to determine whether the drug affects the self-renewal function of ALL-B initiator cells
- In vivo treatment of transgenic mice
- In vivo treatment of B-ALL PDXs (read more)
Terms
OPALE entity
CRCT (UMR-1037)
IGAALD team
Contact
Dr. Sandrine PalcyBusiness Development Director
Other offers
PHARMACODYNAMIC STUDIES FOR THE DEVELOPMENT OF NEW TREATMENTS FOR ACUTE MYELOID LEUKEMIA
PRECLINICAL XENOGRAFT MODELS FOR THE EVALUATION OF NEW COMPOUNDS IN THE TREATMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA B
DEVELOPMENT OF MOLECULAR DIAGNOSTICS KITS FOR GENOMIC ALTERATION IN LEUKEMIA AND OTHER MALIGNANT HEMOPATHIES