title: Computational modelling of anti-angiogenic therapies based on multiparametric molecular imaging data.
abstract: Computational tumour models have emerged as powerful tools for the optimization of cancer therapies; ideally, these models should incorporate patient-specific imaging data indicative of therapeutic response. The purpose of this study was to develop a tumour modelling framework in order to simulate the therapeutic effects of anti-angiogenic agents based upon clinical molecular imaging data. The model was applied to positron emission tomography (PET) data of cellular proliferation and hypoxia from a phase I clinical trial of bevacizumab, an antibody that neutralizes the vascular endothelial growth factor (VEGF). When using pre-therapy PET data in combination with literature-based dose response parameters, simulated follow-up hypoxia data yielded good qualitative agreement with imaged hypoxia levels. Improving the quantitative agreement with follow-up hypoxia and proliferation PET data required tuning of the maximum vascular growth fraction (VGF(max)) and the tumour cell cycle time to patient-specific values. VGF(max) was found to be the most sensitive model parameter (CV = 22%). Assuming availability of patient-specific, intratumoural VEGF levels, we show how bevacizumab dose levels can potentially be 'tailored' to improve levels of tumour hypoxia while maintaining proliferative response, both of which are critically important in the context of combination therapy. Our results suggest that, upon further validation, the application of image-driven computational models may afford opportunities to optimize dosing regimens and combination therapies in a patient-specific manner.
authors.affiliation: Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. titz@wisc.edu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Titz
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kozak
authors.forename: Robert
authors.initials: R
authors.lastname: Jeraj
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000068258:Bevacizumab; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging* / Q000473:pathology; D049268:Positron-Emission Tomography
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab