DEVELOPMENT OF SMALL MOLECULES FOR TARGETED THERAPIES (ALL/AML)

Preclinical development

Targeted therapy

Preclinical research (TRL 4-5)

Translational research platform for the evaluation of small active molecules (or active peptides) for the development of treatments for AML and ALL.

Study of in vitro and in vivo combinations to select and validate molecules (or peptides), combinations of molecules or biomarkers.

Description

Scope of research activities

Preclinical research using in vitro and in vivo models of AML and ALL:

Proof-of-concept validation: evaluation of drug efficacy, stratification of pathology subgroups
Drug combination screening
Identification of biomarkers

Conduct of studies

Step :

Establishing the scope of research partnership in the form of milestones
Update after milestone completion
Go-no go" discussions for future pre-clinical or clinical development

Research infrastructure

Experimental and analytical platforms:

Cell culture laboratory with fume hood, cell culture, flow cytometry, cell sorting, florescence microscopy, access to molecular biology (PCR, microarray, CHIPseq)
AML and ALL cell lines, annotated biobank of AML and ALL patient samples (THEMA cohort), mouse models (xenograft, syngeneic), access to PDX via collaboration
1 permanent engineer and 1 assistant engineer

Specifications

The platform

Screening platform using 3D in vitro models (co-culture of mesenchymal stem cells, blast cells, NK cells) to mimic the complexity of the tumor environment.

Studies

In vitro efficacy studies on primary patient cells (AML/ALL):

MTS, proliferation, apoptosis, autophagy, differentiation, combination index
Feeder culture (fibroblasts, cytokines) of primary ALL cells

In vivo efficacy studies in PDX mouse model (AML/ALL):

Survival
Leukemic expansion by flow cytometry

Combination drug screening using a library of small molecules used in standard care:

NEXT platform with measurement of cytotoxicity, differentiation, effect on bulk and leukemic stem cells

Identification of biomarkers using patient samples and cohort data, in preparation for an early-phase clinical trial:

Biomarker-dependent flow cytometry, PCR, Western blot analysis

Examples of partnerships

New therapeutic strategies in acute leukemia - Cifre Thesis.

Partner: Servier

Preclinical evaluation of potential therapeutic efficacy of the MPS1 inhibitor S81694 in Acute Myelogenous Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) - In this study the preclinical activity of an inhibitor of the MPS1 kinase, a major kinase of the "spindle check point (SAC) was evaluated. The MPS1 inhibitor, S81694, shows promising anti-leukemic activity in different models of ALL and AML, with significant synergy: