A Tumor-in-Host DEB-Based Approach for Modeling Cachexia and Bevacizumab Resistance.
Cancer Res
; 80(4): 820-831, 2020 02 15.
Article
em En
| MEDLINE
| ID: mdl-31818849
ABSTRACT
Adequate energy intake and homeostasis are fundamental for the appropriate growth and maintenance of an organism; the presence of a tumor can break this equilibrium. Tumor energy requests can lead to extreme weight loss in animals and cachexia in cancer patients. Angiogenesis inhibitors, acting on tumor vascularization, counteract this tumor-host energy imbalance, with significant results in preclinical models and more limited results in the clinic. Current pharmacokinetic-pharmacodynamic models mainly focus on the antiangiogenic effects on tumor growth but do not provide information about host conditions. A model that can predict energetic conditions that provide significant tumor growth inhibition with acceptable host body weight reduction is therefore needed. We developed a new tumor-in-host dynamic energy budget (DEB)-based model to account for the cytostatic activity of antiangiogenic treatments. Drug effect was implemented as an inhibition of the energy fraction subtracted from the host by the tumor. The model was tested on seven xenograft experiments involving bevacizumab and three different tumor cell lines. The model successfully predicted tumor and host body growth data, providing a quantitative measurement of drug potency and tumor-related cachexia. The inclusion of a hypoxia-triggered resistance mechanism enabled investigation of the decreased efficacy frequently observed with prolonged bevacizumab treatments. In conclusion, the tumor-in-host DEB-based approach has been extended to account for the effect of bevacizumab. The resistance model predicts the response to different administration protocols and, for the first time, the impact of tumor-related cachexia in different cell lines. Finally, the physiologic base of the model strongly suggests its use in translational human research. SIGNIFICANCE:
A mathematical model describes tumor growth in animal models, taking into consideration the energy balance involving both the growth of tumor and the physiologic functions of the host.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Caquexia
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Inibidores da Angiogênese
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Metabolismo Energético
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Bevacizumab
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Modelos Biológicos
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Neoplasias
Tipo de estudo:
Etiology_studies
/
Guideline
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Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article