Preclinical Modeling of Tumor Growth and Angiogenesis Inhibition to Describe Pazopanib Clinical Effects in Renal Cell Carcinoma.

Abstract

The objective was to leverage tumor size data from preclinical experiments to propose a model of tumor growth and angiogenesis inhibition for the analysis of pazopanib efficacy in renal cell carcinoma (RCC) patients. We analyzed tumor data in mice with RCC CAKI-2 cell line treated with pazopanib. Clinical tumor size data obtained in a subset of patients with RCC were also analyzed. A model accounting for the processes of tumor growth, angiogenesis, and drug effect was developed. The final tumor model was composed of two variables: the tumor and its vasculature. Our results show that, both in mice and in humans, pazopanib exhibits a dual mechanism of action, and parameter estimation values highlight the inherent difference between mice and humans on the time scale of tumor size response. We developed a semimechanistic tumor growth inhibition model that takes into account tumor angiogenesis in order to describe the effects of pazopanib in mice. Analyzing rich preclinical data with a semimechanistic model may be a relevant approach to facilitate the description of sparse clinical longitudinal tumor size data and to provide insights for the understanding of the drug mechanisms of action in patients.