Angiogenesis is the process of new blood vessel formation from preexisting blood vessels. This process plays a central role in both tumor growth and dissemination in a variety of different human cancers. Recently published studies have suggested that a tumor can escape initial VEGF inhibition by altering the regulation of other growth factors which may be important for angiogenesis and tumor cell proliferation. Therefore, to obtain the greatest effects on cell growth reduction it may be beneficial to target more than one pathway. BMS-582664, which is currently under clinical evaluation, is an orally available and selective tyrosine kinase inhibitor that targets two key angiogenesis and tumor growth promoting pathways, VEGF and FGF. Bevacizumab is an antibody that targets only one of these key pathways, VEGF. We compared the effects of both compounds against a xenograft colon cancer (GEO) model at the transcriptional level and cells in vitro as well as in vivo tumor xenografts. Tumor samples were collected from the xenografts and RNA was extracted for gene expression profiling on Affymetrix™ mouse and human genechips. Analysis was performed, using a defined set of genes previously identified to be associated with angiogenesis and tumor cell proliferation between the tumor samples from treated and untreated mice. Transcriptional data showed that both drugs suppressed vascular related genes but only BMS-582664 suppressed tumor cell proliferation genes. In vitro cellular assays confirmed that BMS-582664 could directly inhibit GEO cells stimulated with FGF at an IC50 well below what is required for in vivo antitumor activity. Bevacizumab was unable to show any direct inhibition of the GEO cancer cells in vitro when stimulated with either VEGF or FGF. In addition BMS-582664 was able to inhibit tumor growth in a separate xenograft model, Ht-29 (Colon), which has been previously reported to be non-responsive to Bevacizumab therapy. Additional data on gene expression profiling and efficacy results from the xenografts studies will be presented.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA