A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Half of human cancers involve loss of p53 tumor suppressor function due to missense mutations.
• A subset of these mutations leads to p53 forming amyloid-like aggregates, impairing its function.
• High-grade serous ovarian carcinoma (HGSOC) frequently exhibits p53 mutations.

Purpose of the Study:

• To investigate the potential of targeting p53 amyloid formation as a therapeutic strategy.
• To evaluate the efficacy of a novel peptide, ReACp53, in rescuing p53 function.
• To assess the applicability of this approach in high-grade serous ovarian carcinomas (HGSOC).

Main Methods:

• Design of ReACp53, a cell-penetrating peptide to inhibit p53 amyloid formation.
• Testing ReACp53 in cancer cell lines and HGSOC organoids.
• Assessing p53 target gene regulation, cell proliferation, and cell death.
• In vivo studies involving intraperitoneal administration in xenograft models.

Main Results:

• ReACp53 successfully rescued p53 function in cancer cell lines and HGSOC organoids.
• Rescued p53 exhibited wild-type-like behavior in regulating target genes, reducing proliferation, and inducing cell death.
• Intraperitoneal administration of ReACp53 reduced tumor proliferation and shrank xenografts in vivo.

Conclusions:

• Targeting p53 aggregation defects represents a viable therapeutic strategy.
• ReACp53 demonstrates effectiveness in restoring p53 function and inhibiting tumor growth.
• This approach holds significant potential for the treatment of HGSOC.