title: Modeling Longitudinal Preclinical Tumor Size Data to Identify Transient Dynamics in Tumor Response to Antiangiogenic Drugs.
abstract: Experimental evidence suggests that antiangiogenic therapy gives rise to a transient window of vessel normalization, within which the efficacy of radiotherapy and chemotherapy may be enhanced. Preclinical experiments that measure components of vessel normalization are invasive and expensive. We have developed a mathematical model of vascular tumor growth from preclinical time-course data in a breast cancer xenograft model. We used a mixed-effects approach for model parameterization, leveraging tumor size data to identify a period of enhanced tumor growth that could potentially correspond to the transient window of vessel normalization. We estimated the characteristics of the window for mice treated with an anti-VEGF antibody (bevacizumab) or with a bispecific anti-VEGF/anti-angiopoietin-2 antibody (vanucizumab). We show how the mathematical model could theoretically be used to predict how to coordinate antiangiogenic therapy with radiotherapy or chemotherapy to maximize therapeutic effect, reducing the need for preclinical experiments that directly measure vessel normalization parameters.
authors.affiliation: Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, UK.
authors.forename: L G
authors.initials: LG
authors.lastname: Hutchinson
authors.affiliation: Pharma Research and Early Development, Roche Innovation Centre Munich, Munich, Germany.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Mueller
authors.affiliation: Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, UK.
authors.forename: E A
authors.initials: EA
authors.lastname: Gaffney
authors.affiliation: Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, UK.
authors.forename: P K
authors.initials: PK
authors.lastname: Maini
authors.affiliation: Roche Pharmaceutical Research & Early Development, Roche Innovation Center, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Wagg
authors.affiliation: Pharma Research and Early Development, Roche Innovation, Welwyn Garden City, UK.
authors.forename: A
authors.initials: A
authors.lastname: Phipps
authors.affiliation: Roche Pharmaceutical Research & Early Development, Roche Innovation Center, Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Boetsch
authors.affiliation: Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, UK.
authors.forename: H M
authors.initials: HM
authors.lastname: Byrne
authors.affiliation: Pharma Research and Early Development, Roche Innovation Centre Munich, Munich, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Ribba
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab / Q000494:pharmacology; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D015233:Models, Statistical; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D011897:Random Allocation; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; C000619444:vanucizumab