A PHASE I DOSE-ESCALATION STUDY OF THE SAFETY AND PHARMACOKINETICS OF A NOVEL SPECTRUM SELECTIVE KINASE INHIBITOR, XL820, ADMINISTERED ORALLY TO PATIENTS WITH SOLID TUMORS

■ Several receptor tyrosine kinases (RTKs) are implicated in cancer pathobiology, including KIT, the vascular endothelial growth factor (VEGF) receptors, and the platelet-derived growth factor (PDGF) receptors.These RTKs both directly and indirectly contribute to tumor growth and dissemination.1 ■ VEGF binds to at least three receptors: FLT1 (VEGFR1), KDR (VEGFR2), and FLT4 (VEGFR4). The VEGF receptors FLT1 and KDR are expressed on the surface of vascular endothelial cells and on some bone marrow–derived cells.2 When activated by ligand binding, VEGF receptors mediate endothelial cell invasion, proliferation, and survival. ■ VEGF expression is upregulated in many human tumors, and binding and activation of KDR by VEGF, originating from either tumor or adjacent stromal cells, is likely a major driver of tumor neoangiogenesis. ■ KIT is an RTK that is widely expressed in mast cells. The KIT ligand, stem cell factor (SCF), stimulates mast cell migration, proliferation, and degranulation. Mast cells accumulate in solid tumors and secrete several pro-angiogenic factors, including VEGF. 3 ■ KIT has also been implicated in the pathogenesis of several tumor types, including gastrointestinal stromal tumors (GIST), melanoma, and ovarian cancer