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.
Highlights
Angiogenesis, the development of new capillary blood vessels, plays a key role in the growth and progression of solid tumors [1]
Based on the dynamic energy budget (DEB) theory, we proposed a new tumor-in-host growth inhibition model able to describe and predict the dynamics of both tumor and host net body weight in control and treated xenograft mice following the administration of an angiogenesis inhibitor
This limitation is reported in the clinical setting where a reduced efficacy due to resistance mechanisms is frequently observed during prolonged antiangiogenic administrations [7, 41]
Summary
Angiogenesis, the development of new capillary blood vessels, plays a key role in the growth and progression of solid tumors [1]. Like normal tissues, tumor cells need an adequate supply of oxygen, nutrients, and an effective way to remove waste products [2]. Tumors can directly cause the development of this blood supply or induce nearby normal cells to produce proangiogenic molecules. This dense vascular network ensures to tumor cells the amount of energy needed to proliferate. In a large number of cases, especially in advanced stages of cancer, the homoeostatic control of energy and protein balance is so compromised in favor of tumor to result in a dramatic loss of host body weight, attributable to the decreases of both skeletal muscle (biomass) and adipose tissue (energy reserve). Depletion of skeletal muscle is a key component of cancer-associated cachexia and it is responsible for increased chemotherapy toxicity, complications from cancer surgery, poor quality of life, and mortality [3, 4]
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