NEXT PLATFORM: DRUG COMBINATION SCREENING OF PRIMARY SAMPLES FOR ACUTE MYELOID LEUKEMIA
- Biomarkers
- Leads optimization
- Drug combination identification
- AML
- Precision medicine
- Translational research (TRL 4-5)
Functional precision medicine platform based on high-throughput flow cytometry for drug sensitivity testing and biomarker discovery in acute myeloid leukemia (AML).
Our cutting-edge ex vivo drug sensitivity testing platform offers a unique approach by combining custom ex vivo culture of primary patient samples, to better mimic the leukemia niche with multiparameter flow cytometry. This allows us to measure multiple readouts, including differentiation and T cell activation, in addition to cell viability.
We utilize primary AML samples, including relapsed/refractory (R/R) AMLs, from the ALFA multicenter prospective registry. These samples are enriched with extensive clinical and genetic annotations.
Furthermore, our platform employs high-throughput screening (HTS) and predictive modeling techniques to facilitate lead prioritization. Our Bayesian methods are adept at identifying and optimizing synergistic drug combinations, ensuring a targeted and efficient therapeutic strategy.
Description
Scope of research activities
Preclinical and translational research in AML:
- Lead optimization by testing their activity on primary AML samples
- Drug combination prioritization by testing their activity and synergism on primary AML samples
- Discovery of biomarkers by correlating ex vivo activity with clinical and genetic annotations
- In vivo validation of single agent or combination activity in PDX models
Conduct of studies
Steps :
- Study design
- Define means/resources and propose schedule (steps, GO/NO-GO, cost estimate)
- Study organization, implementation and conduct
- Data analysis and delivery of a study report with recommendations
Research infrastructure
Experimental and analysis platforms:
- Automated liquid dispensing (Biomek i5, Beckmann Coulter)
- Magnetic cell enrichment (MACS, Miltenyi)
- Spectral cell sorting (BigFoot, ThermoFisher)
- High-Throughput Screening flow cytometer (3 lasers, 13 parameters, iQUE3, Sartorius)
- Conventional flow cytometer (2 lasers, 8 parameters, Cytoflex, Beckmann Coulter)
- NSGS and NOG-EXL recipients for PDXs.
Models:
- Primary cells from annotated AML patients (including R/R AMLs) from the ALFA prospective registry, demographics, previous therapies, genetics data
- Human AML cell lines (assay calibration)
- PDX models
Technical personel:
- 1 physician-scientist (scientific supervision, data analysis) and 1 operational engineer manager
- 1 engineer (PDX models)
- 1 engineer and 1 assistant engineer – ex vivo drug testing
Quality assurance
- Université Paris Cité Technology Platforms certification (ongoing)
- Animal Facility at IRSL compliant with European and French Regulation (Directive 2010/63; Décret 2013-118)
Specifications
The platform
Preclinical and translational studies using primary cells from AML patients (or from PDXs), for the investigation of single agent or combination activity and further in vivo validation.
The studies
- Activity of single agent or drug combination on leukemic viability
- Activity of single agent or drug combination on differentiation of leukemic cells
- Differential activity of single agent or drug combination between phenotypically-defined leukemic stem and non-stem cells
- Differential activity of single agent or drug combination between leukemic cells and circulating T cells
- Differential activity of single agent or drug combination between clinically or genetically defined AML patient populations
Examples of partnerships
Preclinical investigation of a first-in-class kinase inhibitor in AML – Ex vivo exploration of single agent activity of a first-in-class kinase inhibitor in AML, prioritization of combinations, in vivo validation in PDX models.
Partner: SERVIER
Preclinical investigation of a first-in-class BET inhibitor in AML – Ex vivo exploration of single agent activity of a first-in-class BET inhibitor in AML, prioritization of combinations, dedicated long term cultures to explore impact on LSCs.
Partner: ONCOETHIX
Terms
OPALE entity
GenCellDis (UMR-944)
Contact
Dr. Sandrine PalcyBusiness Development Director