PHASE I DOSE ESCALATION STUDY TO DETERMINE THE SAFETY,PHARMACOKINETICS AND

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Vascular endothelial growth factor receptor-2 (VEGFR-2) is a cell surface protein tyrosine kinase receptor that is essential for regulating tumor angiogenesis, a rate limiting process in tumor expansion, survival, and dissemination.1,2 The VEGFR-2 kinase is generally restricted to cellular expression on both tumor activated endothelial cells and quiescent (non-proliferating) endothelial cells of mammalian tissues and organs.3,4 More recently, it has been identified in selected subsets of hematopoietic stem cells.5 VEGFR-2 is part of a larger family of receptors that include VEGFR-1 and VEGFR-3.6 VEGFR-2 is the major mediator of multiple steps in tumor angiogenesis that include endothelial cell proliferation, survival, migration, differentiation as well as vascular permeability.1,5,7,8. The cytoplasmic catalytic domain, which is activated by autophosphorylation upon ligand binding, is responsible for substrate phosphorylation implicated in mediating signaling pathways involved in these multiple steps of tumor endothelium activation. In normal tissues, vascular endothelial growth factor (VEGF) Is upregulated and its mRNA stabilized only under conditions of hypoxia. In tumor cells, by contrast, VEGF is constitutively overexpressed, independent of the ambient oxygen tension, but its expression can be further increased by hypoxia, which is commonly present in solid tumors.2 Recently there has also been clinical validation of the anti-tumor activity produced by inhibition of the VEGF pathway. Avastin¿, an anti- VEGF-A antibody, leads to a significant increase in survival when added to chemotherapy for subjects with metastatic colorectal cancer 8, and prolonged time to progression in subjects with renal cancer.9 BMS-540215 is the chemical parent and active moiety of the alanine ester prodrug BMS-582664. It is a selective and potent inhibitor of VEGFR-2 substrate phosphorylation and also has activity against fibroblast growth factor receptor (FGFR-1), another important regulator of angiogenesis. By inhibition of VEGFR-2 and FGFR-1, BMS-540215 and its orally available prodrug inhibit endothelial cell activation. Therefore, it is anticipated to have a therapeutic application in angiogenesis dependent human disease, such as in the treatment of cancer and tumor metastasis. Since a significant proportion of most common cancers overexpression VEGF, the potential activity of agents targeting this pathway is broad. Based on pre-clinical data, BMS-582664 has the potential for therapeutic use in a wide variety of tumors, both as monotherapy and as an add-on to the current standard of care.