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.
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.
Tentler
John J
JJ
Division of Medical Oncology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
Bradshaw-Pierce
Erica L
EL
Departments of Anesthesiology and Radiology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
Serkova
Natalie J
NJ
Departments of Anesthesiology and Radiology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
Hasebroock
Kendra M
KM
Departments of Anesthesiology and Radiology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
Pitts
Todd M
TM
Division of Medical Oncology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
Diamond
Jennifer R
JR
Division of Medical Oncology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
Fletcher
Graham C
GC
EntreMed, Inc., Toronto, Ontario, Canada.
Bray
Mark R
MR
EntreMed, Inc., Toronto, Ontario, Canada.
Eckhardt
S Gail
SG
Division of Medical Oncology, University of Colorado Anschutz Medical Center, Aurora, Colorado.
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
D000970:Antineoplastic Agents; C551397:ENMD 2076; D019394:Ki-67 Antigen; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines
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