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Exploiting the weakness of tumor cells

SIRIC team
01/23/2019
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How to exploit acquired knowledge on tumor biology to identify new therapeutic approaches. A tailored approach for each pathology.
Parcours patient cancers pédiatriques à l'Institut Curie

Combination therapies with ALK inhibitors in neuroblastoma

G Schleiermacher

Evolution of tumor cell subclones in neuroblastoma
Illustration of the evolution of different tumor cell clones during treatment. One of the two subclones (in red) from the primary tumor is resistant to the first line of chemotherapy and becomes predominant at 158 days

Background: The team has recently demonstrated that sub-clones of ALK-mutated cancer cells in neuroblastoma could be present at diagnosis and then appear amplified at relapse.

Hypothesis: Knowing that ALK inhibitors are already part of the therapeutic arsenal in other pathologies the use of these targeted therapies from the first lines of treatment could avoid a certain number of relapses.

Objective: Test ALK inhibitors on cell lines in combination with first-line treatment with the aim of introducing this approach to clinical practice.

Destabilizing the ESWR1-FLI1 oncogene in Ewing sarcoma

O Delattre et K Laud

Déstabilisation de l'oncogène EXSR-FLI1 dans le sarcome d'Ewing

Background: Ewing sarcoma is generally characterized by a fusion between the EWSR1 and FLI1 genes. This gene fusion leads to the formation of a chimeric protein EWSR1-FLI. The team has recently perfected a Ewing cell line containing the fusion gene EWSR1-FLI marked with a fluorochrome.

Hypothesis: Modifying the fusion gene expression and monitoring the consequence of this action with the help of fluorochrome could enable us to better understand the disease and envisage new therapeutic options.

Objective: Systematically study the impact of pharmacological reagents on the expression level of the chimeric protein in the cell line. The use of the fluorochrome marker will allow us to carry out a large study on the Biophenics screening platform.

Image: "Creation of a fluorescent labelled fusion protein using genomic editing by CRISPR-Cas9"Karine Laud / Institut Curie (A) Genome editing strategy: Double CRISPR/Cas9 gene targeting using single guide RNA (sgRNA) directed against exonic regions flanking the fusion breakpoint allow inserting a TdTomato cassette in EWSR1-FLI1 fusion gene following homologous recombination. (B) Representative images of fluorescence obtained with the TdTomato-labelled EWSR1-FLI1; left panel: DAPI marking cell nuclei; red panel: Cy3 fluorescence of Tdt-labelled EWSR1-FLI1.

Seeking vulnerabilities in the context of STAG2 mutations in Ewing sarcoma

O Delattre et D Surdez

Cellules métastatiques du sarcome d'Ewing

Background: STAG2 gene mutations are the most frequent secondary mutations in Ewing sarcoma and are generally associated with a poorer survival rate. Using CRISPR techniques the team generated multiple STAG2 proficient or deficient Ewing sarcoma cell lines.

Synthetic lethality is a cell death resulting from the combination of two mutations, each of these mutations being viable when present alone in the cell. A therapeutic strategy would consist of inducing a second mutation within a cell that already has a known mutation.

Hypothesis: Inducing targeted mutation within STAG2 deficient cell lines should allow us to identify synthetic lethal events leading to new therapeutic options and identification of critical signaling pathways.

Objective: Test a series of pharmaceutical compounds or the induction of targeted mutations using the CRISPR technique on STAG2 deficient cell lines.

Tyrosine kinase inhibitors in rhabdoid tumors

F Bourdeaut

Background: During a large-scale test on rhabdoid tumor cell lines Franck Bourdeaut’s team demonstrated the interest of tyrosine kinase inhibitors for new therapeutic approaches.

The EZH2 complex had previously been identified as a key actor of the carcinogenesis process.

Hypothesis: More studies are necessary to be able to envisage clinical trials.

The use of patient derived xenografts (PDXs) should enable us to conduct the necessary studies without tissue limitation.

Objective: Study the action mechanisms of tyrosine kinase inhibitors and test a synthetic lethality targeting the EZH2 complex.

Proteomics as a novel approach to seek new therapeutic targets

O Ayrault and I Janoueix-Lerosey

Project 1

Background: The team have perfected a new technique permitting the analysis of proteins produced by cells (mass spectrometry then immunoprecipitations and enrichment of phosphor peptides using titanium dioxide beads)

Hypothesis: The use of this technique on cell lines in which the ALK gene can be modulated by a pharmacological inhibitor or by an antibody would enable us to study the proteins involved before the ALK signaling pathway.

Objective: Better understand the mechanisms of the disease and eventually identify new therapeutic approaches.

 

Project 2

Background: In medulloblastoma Olivier Ayrault’s team is developing a multi-scale modeling project including complete proteomic and phospho proteomic analyses for the first time.

Hypothesis: the technique described in the previous project should generated precise and detailed models

Objective: Develop a new analysis approach to better understand the disease

Projects of the pediatric cancers program