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.).