Model-based evaluation of image-guided fractionated whole-brain radiation therapy in pediatric diffuse intrinsic
Hillary R Husband1,2, Olivia Campagne1, Chen He3
1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Abstract:
Radiation therapy (RT) is currently the standard treatment for diffuse intrinsic pontine glioma (DIPG), the most common cause of death in children with brain cancer. A pharmacodynamic model was developed to describe the radiation-induced tumor shrinkage and overall survival in mice bearing DIPG. CD1-nude mice were implanted in the brain cortex with luciferase-labeled patient-derived orthotopic xenografts of DIPG (SJDIPGx7 H3F3AWT / K27 M and SJDIPGx37 H3F3AK27M / K27M ). Mice were treated with image-guided whole-brain RT at 1 or 2 Gy/fraction 5-days-on 2-days-off for a cumulative dose of 20 or 54 Gy. Tumor progression was monitored with bioluminescent imaging (BLI). A mathematical model describing BLI and overall survival was developed with data from mice receiving 2 Gy/fraction and validated using data from mice receiving 1 Gy/fraction. BLI data were adequately fitted with a logistic tumor growth function and a signal distribution model with linear radiation-induced killing effect. A higher tumor growth rate in SJDIPGx37 versus SJDIPGx7 xenografts and a killing effect decreasing with higher tumor baseline (p < 0.0001) were identified. Cumulative radiation dose was suggested to inhibit the tumor growth rate according to a Hill function. Survival distribution was best described with a Weibull hazard function in which the hazard baseline was a continuous function of tumor BLI. Significant differences were further identified between DIPG cell lines and untreated versus treated mice. The model was adequately validated with mice receiving 1 Gy/fraction and will be useful in guiding future preclinical trials incorporating radiation and to support systemic combination therapies with RT.
Insights
A new mathematical model describes how radiation therapy affects diffuse intrinsic pontine glioma (DIPG) tumor growth and survival in mice. This model can guide future preclinical trials for this pediatric brain cancer.
Area of Science:
- * Oncology
- * Radiotherapy
- * Mathematical Modeling
Background:
- * Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain cancer, with radiation therapy (RT) as the standard treatment.
- * Understanding the pharmacodynamics of RT in DIPG is crucial for optimizing treatment strategies.
- * Patient-derived xenografts in mice provide a valuable preclinical model for studying DIPG and RT response.
Purpose of the Study:
- * To develop and validate a pharmacodynamic model for radiation-induced tumor shrinkage and survival in DIPG xenografts.
- * To quantify the relationship between radiation dose, tumor growth rate, and overall survival.
- * To provide a tool for guiding future preclinical radiation therapy trials and combination therapies for DIPG.
Main Methods:
- * Orthotopic xenografts of two DIPG patient-derived cell lines (SJDIPGx7 and SJDIPGx37) were established in CD1-nude mice.
- * Mice received image-guided whole-brain radiation therapy (RT) at cumulative doses of 20 or 54 Gy (1 or 2 Gy/fraction).
- * Tumor progression was monitored using bioluminescent imaging (BLI), and a mathematical model was developed to describe BLI and survival data.
Main Results:
- * A logistic tumor growth function and a linear radiation-induced killing effect adequately modeled BLI data.
- * SJDIPGx37 xenografts exhibited a higher growth rate than SJDIPGx7, with radiation's killing effect decreasing at higher baseline tumor burdens.
- * Cumulative radiation dose inhibited tumor growth rate (Hill function), and survival was best described by a Weibull hazard function linked to tumor BLI.
Conclusions:
- * The developed pharmacodynamic model accurately describes radiation effects on DIPG xenografts and overall survival.
- * Significant differences in response were observed between DIPG cell lines and between treated and untreated mice.
- * The validated model is a valuable tool for optimizing RT protocols and supporting the development of novel combination therapies for DIPG.
