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 VEGFR2, cKit and FGFR1, against murine xenograft models of human colorectal cancer (CRC).

HT-29 CRC cell line xenografts were treated with either vehicle or ENMD-2076 (100 mg/kg or 200 mg/kg) orally daily for 28 days. Tumor growth inhibition, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18FDG-positron emission tomography (18FDG-PET) 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.

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 DCE-MRI. PET scanning demonstrated significant decreases in 18FDG 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.

ENMD-2076 demonstrated 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.

PMID: 20406842 [PubMed - as supplied by publisher] Source: National Library of Medicine.