Model‐based evaluation of image‐guided fractionated whole‐brain radiation therapy in pediatric diffuse intrinsic pontine glioma xenografts

Husband, Hillary R.; Campagne, Olivia; He, Chen; Zhu, Xiaoyan; Bianski, Brandon; Baker, Suzanne J.; Shelat, Anang A.; Tinkle, Christopher L.; Stewart, Clinton F.

doi:10.1002/psp4.12627

Cited by 3 publications

(3 citation statements)

References 31 publications

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“…Our radiation and radiosensitizing model can describe xenograft data for different radiosensitizing agents and across multiple studies. Recently, it has also been used to model diffuse intrinsic pontine glioma xenograft data [ 52 ]. The model was able to distinguish between tumor eradication and regrowth for all individuals in all studies.…”

Section: Discussionmentioning

confidence: 99%

Model-based assessment of combination therapies – ranking of radiosensitizing agents in oncology

et al. 2023

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Background To increase the chances of finding efficacious anticancer drugs, improve development times and reduce costs, it is of interest to rank test compounds based on their potential for human use as early as possible in the drug development process. In this paper, we present a method for ranking radiosensitizers using preclinical data. Methods We used data from three xenograft mice studies to calibrate a model that accounts for radiation treatment combined with radiosensitizers. A nonlinear mixed effects approach was utilized where between-subject variability and inter-study variability were considered. Using the calibrated model, we ranked three different Ataxia telangiectasia-mutated inhibitors in terms of anticancer activity. The ranking was based on the Tumor Static Exposure (TSE) concept and primarily illustrated through TSE-curves. Results The model described data well and the predicted number of eradicated tumors was in good agreement with experimental data. The efficacy of the radiosensitizers was evaluated for the median individual and the 95% population percentile. Simulations predicted that a total dose of 220 Gy (5 radiation sessions a week for 6 weeks) was required for 95% of tumors to be eradicated when radiation was given alone. When radiation was combined with doses that achieved at least 8 $$\mu \mathrm{g}/\mathrm{mL}$$ μ g / mL of each radiosensitizer in mouse blood, it was predicted that the radiation dose could be decreased to 50, 65, and 100 Gy, respectively, while maintaining 95% eradication. Conclusions A simulation-based method for calculating TSE-curves was developed, which provides more accurate predictions of tumor eradication than earlier, analytically derived, TSE-curves. The tool we present can potentially be used for radiosensitizer selection before proceeding to subsequent phases of the drug discovery and development process.

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Section: Discussionmentioning

confidence: 99%

Model-based assessment of combination therapies – ranking of radiosensitizing agents in oncology

et al. 2023

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“…Like many tumor models used preclinically, our model contains a sequence of damage compartments [ 26 , 27 , 29 , 45 ], and can be viewed as a combination of these models with the linear-quadratic model in radiobiology [ 15 ], or compartment radiation models that implement the linear-quadratic model with delay [ 21 , 22 ]. Compared with systems pharmacology models for radiation and chemical combinations, e.g., Checkley et al [ 17 ], Kosinsky et al [ 16 ], our model is simpler and, although less mechanistic, can be calibrated to standard xenograft data.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, Husband et al . developed and evaluated radiation models that describe tumor growth and survival in patient-derived xenograft mice for diffuse intrinsic pontine glioma [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Exposure-response modeling improves selection of radiation and radiosensitizer combinations

Cardilin

Almquist

Jirstrand

et al. 2021

J Pharmacokinet Pharmacodyn

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A central question in drug discovery is how to select drug candidates from a large number of available compounds. This analysis presents a model-based approach for comparing and ranking combinations of radiation and radiosensitizers. The approach is quantitative and based on the previously-derived Tumor Static Exposure (TSE) concept. Combinations of radiation and radiosensitizers are evaluated based on their ability to induce tumor regression relative to toxicity and other potential costs. The approach is presented in the form of a case study where the objective is to find the most promising candidate out of three radiosensitizing agents. Data from a xenograft study is described using a nonlinear mixed-effects modeling approach and a previously-published tumor model for radiation and radiosensitizing agents. First, the most promising candidate is chosen under the assumption that all compounds are equally toxic. The impact of toxicity in compound selection is then illustrated by assuming that one compound is more toxic than the others, leading to a different choice of candidate.

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ATM inhibition enhances the efficacy of radiation across distinct molecular subgroups of pediatric high-grade glioma

et al. 2023

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Background Pediatric high-grade glioma (pHGG) is largely incurable and accounts for most brain tumor–related deaths in children. Radiation is a standard therapy, yet the benefit from this treatment modality is transient, and most children succumb to disease within 2 years. Recent large-scale genomic studies suggest that pHGG have alterations in DNA damage response (DDR) pathways that induce resistance to DNA damaging agents. The aim of this study was to evaluate the therapeutic potential and molecular consequences of combining radiation with selective DDR inhibition in pHGG. Methods We conducted an unbiased screen in pHGG cells that combined radiation with clinical candidates targeting the DDR and identified the ATM inhibitor AZD1390. Subsequently, we profiled AZD1390 + radiation in an extensive panel of early passage pHGG cell lines, mechanistically characterized response to the combination in vitro in sensitive and resistant cells and evaluated the combination in vivo using TP53 wild-type and TP53 mutant orthotopic xenografts. Results AZD1390 significantly potentiated radiation across molecular subgroups of pHGG by increasing mutagenic non-homologous end joining and augmenting genomic instability. In contrast to previous reports, ATM inhibition significantly improved the efficacy of radiation in both TP53 wild-type and TP53 mutant isogenic cell lines and distinct orthotopic xenograft models. Furthermore, we identified a novel mechanism of resistance to AZD1390 + radiation that was marked by an attenuated ATM pathway response which dampened sensitivity to ATM inhibition and induced synthetic lethality with ATR inhibition. Conclusions Our study supports the clinical evaluation of AZD1390 in combination with radiation in pediatric patients with HGG.

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Model‐based evaluation of image‐guided fractionated whole‐brain radiation therapy in pediatric diffuse intrinsic pontine glioma xenografts

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 3 publications

References 31 publications

Model-based assessment of combination therapies – ranking of radiosensitizing agents in oncology

Model-based assessment of combination therapies – ranking of radiosensitizing agents in oncology

Exposure-response modeling improves selection of radiation and radiosensitizer combinations

ATM inhibition enhances the efficacy of radiation across distinct molecular subgroups of pediatric high-grade glioma

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