APR-246 as a radiosensitization strategy for mutant p53 cancers treated with alpha-particles-based radiotherapy

Area of Science:

• Oncology
• Radiation Oncology
• Cancer Genetics

Background:

• Radiation therapy (RT) is a cornerstone of cancer treatment, but challenges remain in targeting tumors effectively.
• High-linear energy transfer (high-LET) radiation, like alpha particles, induces potent DNA damage but has limited range.
• Mutations in the TP53 tumor suppressor gene are common in human cancers and often confer resistance to conventional therapies.

Purpose of the Study:

• To investigate the efficacy of combining alpha-particle-based RT using Radium-224 (224Ra) with APR-246, a p53 reactivating compound.
• To evaluate this combination therapy in preclinical models of colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) with mutant p53.
• To assess the impact on cancer cell survival, tumor growth, and the spatial distribution of cell death.

Main Methods:

• Utilized cellular models and tumor xenografts of CRC and PDAC harboring mutant p53.
• Administered alpha-particle irradiation and systemic APR-246 treatment, both individually and in combination.
• Assessed cell survival, tumor growth inhibition, tumor eradication rates, alpha-emitter distribution, and apoptosis patterns.

Main Results:

• Mutant p53 cancer cells demonstrated radiosensitivity to alpha particles in vitro and in vivo.
• APR-246 treatment significantly enhanced sensitivity to alpha-particle RT.
• The combination therapy led to reduced tumor growth and increased tumor eradication, with enhanced cell death observed.

Conclusions:

• Combining alpha-particle RT with p53 restoration via APR-246 is a promising strategy for treating mutant p53 cancers.
• This approach triggers significant cell death and improves therapeutic outcomes in preclinical models.
• Further investigation is warranted to translate these findings into clinical applications for patients with mutant p53 tumors.