Cancer therapeutic approach based on conformational stabilization of mutant p53 protein by small peptides

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• The p53 tumor suppressor is crucial in preventing cancer, but over 50% of human tumors inactivate it via mutations.
• Mutations often destabilize p53, leading to misfolding and loss of function at body temperature.
• Restoring native p53 folding could reactivate its tumor-suppressive activity.

Purpose of the Study:

• To identify peptides that can stabilize the native conformation of mutant p53 (mutp53).
• To restore wild-type p53 activity in cancer cells.
• To evaluate the therapeutic potential of these reactivating peptides.

Main Methods:

• Utilized phage display technology to screen random peptide libraries against mutp53.
• Enriched phages displaying peptides that favor the correctly folded p53 conformation.
• Synthesized lead peptides and assessed their ability to restore p53 folding and activity.

Main Results:

• Identified numerous peptides capable of interacting with and potentially stabilizing mutp53.
• Discovered that some lead peptides correspond to known p53-binding proteins, such as RAD9.
• Demonstrated significant tumor regression in aggressive cancer xenograft models using these peptides.

Conclusions:

• Peptides can be selected to refold and reactivate mutant p53.
• Identified peptides, including those related to RAD9, show therapeutic potential.
• These peptides represent a novel strategy for human cancer therapy by restoring p53 function.