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

Sep 21, 2026

Uploaded by Maeve

Radiation therapy remains widely used, but achieving lethal tumor dosing while sparing healthy tissue is challenging. Alpha particles (high-LET) can induce clustered DNA double-strand breaks that may drive cells toward apoptosis more effectively, yet their short tissue range limits prior development. This study combines Radium-224 (224Ra)–based alpha-emitting radiotherapy with systemic APR-246, a p53 reactivating compound, to treat mutant TP53 tumors and evaluate effects on survival, tumor growth, alpha emitter spread, and apoptosis localization. Results show enhanced radio-sensitivity, reduced tumor growth, and improved tumor eradication, supporting further preclinical and clinical validation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Introduction

Radiation therapy challenges: LET and DNA damage

Radiosensitizers and p53 biology

Study rationale for combining 224Ra and APR-246

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN APR-246 as a radiosensitization strategy for mutant p53 cancers treated with alpha-particles-based radiotherapy Or Michaeli1, Ishai Luz 1, Maayan Vatarescu 1,2, Tal Manko 1, Noam Weizman3, Yevgeniya Korotinsky3, Alexandra Tsitrina4, Alex Braiman 1, Lior Arazi3 and Tomer Cooks 1 ✉ © The Author(s) 2024 | | Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs. The challenge in RT lies in delivering a lethal dose to the cancerous site while sparing the surrounding healthy tissues. Low linear energy transfer (low-LET) and high linear energy transfer (high-LET) radiations have distinct effects on cells. High-LET radiation, such as alpha particles, induces clustered DNA double-strand breaks (DSBs), potentially inducing cell death more effectively. However, due to limited range, alpha-particle therapies have been restricted. In human cancer, mutations in TP53 (encoding for the p53 tumor suppressor) are the most common genetic alteration. It was previously reported that cells carrying wild-type (WT) p53 exhibit accelerated senescence and signiﬁcant rates of apoptosis in response to RT, whereas cells harboring mutant p53 (mutp53) do not. This study investigated the combination of the alpha-emitting atoms RT based on internal Radium-224 (224Ra) sources and systemic APR-246 (a p53 reactivating compound) to treat tumors with mutant p53 . Cellular models of colorectal cancer (CRC) or pancreatic ductal adenocarcinoma (PDAC) harboring mutant p53, were exposed to alpha particles, and tumor xenografts with mutant p53 were treated using 224Ra source and APR-246 . Effects on cell survival and tumor growth, were assessed. The spread of alpha emitters in tumors was also evaluated as well as the spatial distribution of apoptosis within the treated tumors. We show that mutant p53 cancer cells exhibit radio-sensitivity to alpha particles in vitro and to alphaparticles-based RT in vivo. APR-246 treatment enhanced sensitivity to alpha radiation, leading to reduced tumor growth and increased rates of tumor eradication. Combining alpha-particles-based RT with p53 restoration via APR-246 triggered cell death, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for | | | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | improving treatment outcomes in patients with mutant p53 tumors. | | | | | Cell Death and Disease (2024)15:426; [https://doi.org/10.1038/s41419-024-06830-3](https://doi.org/10.1038/s41419-024-06830-3) | | | | | | INTRODUCTION Alongside many other commonly used anti-cancer strategies and despite recently developed modalities that include targeted biological compounds and immunotherapeutic drugs, most cancer patients worldwide are still treated with some form of radiation therapy (RT), either as a main treatment or as anadjuvant approach [1–3] . The major challenge in RT lies in the delicate balance between delivering a destructive, lethal dose into the cancerous tissue while limiting the damage to the surrounding healthy perimeters and the radiotoxicity affecting vital organs. To that end, the use of low versus high linear energy transfer (low-LET and high-LET) differs signiﬁcantly [4–6] . While 1 Gray (Gy) dose of X-rays (low-LET) induces thousands of single-strand breaks (SSBs) to the DNA of a mammalian cell and approximately 40 double strand breaks (DSBs), as LET increases, so does cytotoxicity [7, 8] . Notably, only a few hits of alpha particles (high-LET) to the DNA can produce clustered DSBs that will drive the cell towards anapoptotic course, mainly due to their high ionization density. Clustered DSBs are repaired less efﬁciently than is

FAQs

Why are alpha particles considered promising for radiotherapy in this work?

Alpha particles are high-LET radiation that can produce clustered DNA double-strand breaks, which are repaired less efficiently and can better drive apoptosis compared with low-LET radiation.

What is APR-246 in the proposed treatment strategy?

APR-246 is described as a p53 reactivating compound, intended to restore or enhance p53-related responses that support apoptosis and improved sensitivity to radiation.

How was the combination therapy evaluated in mutant p53 tumor models?

Cellular colorectal cancer and pancreatic ductal adenocarcinoma models with mutant p53 were exposed to alpha particles, and mutant p53 tumor xenografts were treated using a 224Ra source plus APR-246; outcomes included cell survival, tumor growth, alpha emitter distribution, and spatial apoptosis patterns.

Sep 21, 2026

Uploaded by Maeve