title: Assessment of the in vivo antitumor effects of ENMD-2076, a novel multitargeted kinase inhibitor, against primary and cell line-derived human colorectal cancer xenograft models.
abstract: OBJECTIVE
  This in vivo study was designed to investigate the efficacy of ENMD-2076, a small-molecule kinase inhibitor with activity against the Aurora kinases A and B, and several other tyrosine kinases linked to cancer, including vascular endothelial growth factor receptor 2, cKit, and fibroblast growth factor receptor 1, against murine xenograft models of human colorectal cancer (CRC).
  
  
  METHODS
  HT-29 CRC cell line xenografts were treated with either vehicle or ENMD-2076 (100 or 200 mg/kg) orally daily for 28 days. Tumor growth inhibition, dynamic contrast-enhanced magnetic resonance imaging, and (18)FDG-positron emission tomography were conducted to assess the antiproliferative, antiangiogenic, and antimetabolic responses, respectively. Effects on proliferation were also analyzed by immunohistochemical methods. Additionally, three patient-derived xenografts from primary and metastatic sites were treated with ENMD-2076 (100 mg/kg) and assessed for tumor growth inhibition.
  
  
  RESULTS
  In the HT-29 xenograft model, ENMD-2076 induced initial tumor growth inhibition followed by regression. Treatment was associated with significant tumor blanching, indicating a loss of vascularity and substantial reductions in tumor vascular permeability and perfusion as measured by dynamic contrast-enhanced magnetic resonance imaging. Positron emission tomography scanning showed significant decreases in (18)FDG uptake at days 3 and 21 of treatment, which was associated with a marked reduction in proliferation as assessed by Ki-67. All three of the patient-derived xenografts tested were sensitive to treatment with ENMD 2076 as measured by tumor growth inhibition.
  
  
  CONCLUSIONS
  ENMD-2076 showed robust antitumor activity against cell line and patient-derived xenograft models of CRC that is detectable by functional imaging, supporting clinical investigation of this agent in CRC.
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
authors.forename: John J
authors.initials: JJ
authors.lastname: Tentler
authors.affiliation: Departments of Anesthesiology and Radiology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Bradshaw-Pierce
authors.affiliation: Departments of Anesthesiology and Radiology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Serkova
authors.affiliation: Departments of Anesthesiology and Radiology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
authors.forename: Kendra M
authors.initials: KM
authors.lastname: Hasebroock
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Pitts
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Diamond
authors.affiliation: EntreMed, Inc., Toronto, Ontario, Canada.
authors.forename: Graham C
authors.initials: GC
authors.lastname: Fletcher
authors.affiliation: EntreMed, Inc., Toronto, Ontario, Canada.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bray
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D005260:Female; D019073:HT29 Cells; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C551397:ENMD 2076; D019394:Ki-67 Antigen; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines
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