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Modeling the Acute Mucosal Toxicity of Fractionated Radiotherapy Combined with the ATM Inhibitor WSD0628
Darwin A Garcia1, Sneha Rathi2, Margaret A Connors1
1Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
Molecular Cancer Therapeutics
|November 19, 2024
Summary
Ataxia Telangiectasia-mutated (ATM) inhibitors like WSD0628 significantly increase radiation toxicity in normal tissues. This study models these effects to guide safer radiosensitizer development and radiotherapy planning.
Area of Science:
- Radiation Oncology
- Pharmacology
- Toxicology
Background:
- Ataxia Telangiectasia-mutated (ATM) inhibitors enhance radiotherapy's antitumor effects but risk normal tissue radiosensitization.
- Understanding and mitigating normal tissue toxicities are crucial for developing effective ATM inhibitor radiosensitizers.
Purpose of the Study:
- To model the relationship between acute mucosal toxicity, radiation dose, fractionation, and ATM inhibitor exposure.
- To quantify the radiosensitizing effect of the ATM inhibitor WSD0628 on normal tissues.
Main Methods:
- Friend Leukemia virus B (FVB) mice received single or fractionated radiation doses to the oral cavity or esophagus, combined with the ATM inhibitor WSD0628.
- The sensitizer enhancement ratio (SER) was calculated to quantify WSD0628's potentiation of radiation-induced toxicities.
Main Results:
- WSD0628 significantly enhanced acute oral and esophageal toxicities.
- For oral toxicity, SER ranged from 1.3 to 3.1 with 3 fractions of radiation, increasing with WSD0628 dose.
- Higher WSD0628 doses and fraction numbers reduced the normal tissue sparing benefit of fractionated radiation, with SERs up to 4.3.
Conclusions:
- ATM inhibitors like WSD0628 profoundly increase normal tissue toxicity, diminishing the benefits of radiation fractionation.
- A modified biologically effective dose model was developed to guide alternative radiation schedules.
- Safe radiosensitizer dose escalation requires careful consideration of tumor site and organ-at-risk dose constraints.
