The interaction between intracellular caspase 9 and serine/threonine phosphatase PP2A proteins is critical to apoptosis. We have designed a Cell Penetrating and Interfering Peptide (CP and IP), Mut3DPT-C9, which specifically disrupt the interaction caspase 9/PP2A and evaluated its therapeutic potential in vitro and in vivo using Patient Derived Xenograft models (PDX). The peptide Mut3DPT-C9 induces caspase 9-dependent apoptosis in cancer cell lines and significant tumor growth inhibition in PDX models of triple-negative breast cancer and hormone-positive HER2 negative breast cancer adenocarcinoma. The peptide specifically induces the death of tumor cells without harm to healthy cells. In addition, neither acute and chronic toxicity nor immunogenic responses were observed, even at high doses.
We also analyzed the stability in serum and the pharmacokinetic parameters in mice and performed optimization on its in vivo stability. Point mutations on a protease cleavage site clearly improved peptide stability while keeping the functional activity. Biodistribution studies demonstrated that the modified peptide is able to reach the target tumor and accumulate there at higher concentration than parental peptide. These results strong suggest that Mut3DPT-C9 peptide constitutes a novel therapeutic approach for the treatment of breast cancer patients.
Audience take away:
Protein/protein interactions (PPIs) are well recognized as promising therapeutic targets. Consequently, interfering peptides capable of interfering PPIs are receiving increasing attention. In addition, progress on peptide administration, stability, biodelibery and safety are also encouraging the interest in peptide drug development. We consider that our results are of interest for the scientific community working on cancer, cell penetrating peptides, interfering peptides, apoptosis and new therapies against cancer.