Specific targeting of caspase-9/PP2A interaction in tumor cells without effect on healthy cells as a new anti-tumoral strategy – PEP-Pharma
The serine/threonine phosphatase PP2A is involved in several cellular processes, including apoptosis. We have shown a direct interaction between caspase-9 and PP2A and developed a cell penetrating peptide (DPT-C9h) that specifically blocks this protein/protein interaction. We have clearly demonstrated that DPT-C9h blocks in vitro and in vivo caspase-9/PP2 interaction and induces caspase-9-dependent apoptosis in B cells from chronic lymphocytic leukemia (CLL) and in human xenograft models of breast. In addition, the peptide does not have neither toxic nor immunogenic effect. We have optimized DPT-C9h peptide and generated a new mutant, Mut3DPT-C9h highly stable in human serum, compared to the original peptide. Our project therefore proposes:
1- To analyze the pharmacokinetic behaviour and biodistribution of Mut3DPT-C9h peptide and other mutated candidates.
2- To validate in vivo the therapeutic use of the peptide using primary human breast cancer xenografts.
3- To identify predictive biomarkers of response to Mut3DPT-C9h peptide.
The results of this project will allow us to formally identify a new penetrating peptide as an innovative antitumor therapeutic approach, validate its efficacy against breast cancers and identify patients who might benefit from this new selective anti-tumor treatment. The proof-of-principle of first generated specific caspse-9/PP2A peptide has already been performed and the results sent for publication (Arrous et al.).
Madame Angelita Rebollo (Immunité et infection - Equipe 6: Biologie et Immunité, Interactions Cellulaires et Moléculaires des Infections Parasitaires et Fongiques.) – email@example.com
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
CERVI Immunité et infection - Equipe 6: Biologie et Immunité, Interactions Cellulaires et Moléculaires des Infections Parasitaires et Fongiques.
LIP Institut Curie - Laboratoire d'investigation préclinique
UPMC-DGRTT Université Pierre et Marie Curie (Paris 6)
Help of the ANR 257,192 euros
Beginning and duration of the scientific project: August 2012 - 24 Months