title: Neoadjuvant antiangiogenic therapy reveals contrasts in primary and metastatic tumor efficacy.
abstract: Thousands of cancer patients are currently in clinical trials evaluating antiangiogenic therapy in the neoadjuvant setting, which is the treatment of localized primary tumors prior to surgical intervention. The rationale is that shrinking a tumor will improve surgical outcomes and minimize growth of occult micrometastatic disease-thus delaying post-surgical recurrence and improving survival. But approved VEGF pathway inhibitors have not been tested in clinically relevant neoadjuvant models that compare pre- and post-surgical treatment effects. Using mouse models of breast, kidney, and melanoma metastasis, we demonstrate that primary tumor responses to neoadjuvant VEGFR TKI treatment do not consistently correlate with improved post-surgical survival, with survival worsened in certain settings. Similar negative effects did not extend to protein-based VEGF pathway inhibitors and could be reversed with altered dose, surgical timing, and treatment duration, or when VEGFR TKIs are combined with metronomic 'anti-metastatic' chemotherapy regimens. These studies represent the first attempt to recapitulate the complex clinical parameters of neoadjuvant therapy in mice and identify a novel tool to compare systemic antiangiogenic treatment effects on localized and disseminated disease.
authors.affiliation: Genitourinary Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA John.Ebos@roswellpark.org.
authors.forename: John M L
authors.initials: JM
authors.lastname: Ebos
authors.affiliation: Genitourinary Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Michalis
authors.initials: M
authors.lastname: Mastri
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Lee
authors.affiliation: Genitourinary Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Tracz
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
authors.forename: John M
authors.initials: JM
authors.lastname: Hudson
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Attwood
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
authors.forename: William R
authors.initials: WR
authors.lastname: Cruz-Munoz
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Jedeszko
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Burns
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D051379:Mice; D016513:Mice, SCID; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage*; D000077210:Sunitinib; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000077210:Sunitinib
keywords: VEGF; antibodies; neoadjuvant; surgery; tyrosine kinase inhibitors