Bringing p53 Back: A Prion-Powered Attack on Retinoblastoma

Area of Science:

• Oncology
• Ophthalmology
• Biotechnology
• Drug Delivery

Background:

• Retinoblastoma (RB) is the most common pediatric intraocular cancer, necessitating treatments that balance tumor eradication with vision preservation.
• Existing chemotherapy, like melphalan, presents challenges due to systemic toxicity and ocular side effects, highlighting the need for targeted therapies.

Purpose of the Study:

• To design and evaluate a prion-like self-assembling peptide prodrug (Pri-MP) for targeted retinoblastoma therapy.
• To leverage RB cell macropinocytosis for selective drug delivery and p53 pathway restoration.

Main Methods:

• Single-cell RNA sequencing identified Rac1-PAK1 signaling as crucial for RB-specific macropinocytosis.
• Pri-MP was designed to exploit macropinocytosis for intracellular accumulation via Au(I)-mediated assembly.
• In vitro and in vivo (orthotopic mouse model) studies assessed Pri-MP's efficacy, safety, and mechanism of action.

Main Results:

• Pri-MP demonstrated potent p53-dependent apoptosis, cell cycle arrest, and tumor suppression in vitro.
• Intravitreal Pri-MP significantly reduced tumor burden in a mouse model with no systemic toxicity or ocular damage.
• Combination therapy with melphalan showed enhanced antitumor activity.
• Pri-MP was shown to antagonize HDMX, reactivating p53 and inducing pro-apoptotic programs.

Conclusions:

• Pri-MP offers a highly specific and safe approach for retinoblastoma treatment by utilizing prion-inspired delivery for tumor-specific p53 reactivation.
• This platform shows potential for eye-preserving therapy in retinoblastoma and may be applicable to other neuroectodermal malignancies.
• Further clinical investigation is warranted to establish Pri-MP as a next-generation treatment for pediatric eye cancer.