Targeted inhibition of angiogenesis in myelodysplastic s

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Description (provided by applicant) The MDSs represent some of the most common hematologic malignancies, with an incidence that approximates that for chronic lymphocytic leukemia. Given the aging of the United States population and the absence of a standard effective treatment for these disorders, management of patients with MUDS has become increasingly problematic. The MDSs share the distinguishing features of ineffective hematopoiesis and increased risk of leukemia transformation. Recent studies have shown that these disorders display an increase in bone marrow (EM) microvessel density, the magnitude of which directly correlates with myeloblast percentage. We have shown that vascular endothelial growth factor (VEGF) and its receptors are expressed by myelomonocytic precursors in MDS and acute myelogenous leukemia (AML), and that VEGF elaboration contributes to suppression of committed progenitor growth and excess medullary generation of TNF alpha. Using the VEGF-receptor competent KG-1 AML cells as a model, we have characterized the biologic effects of VEGF in AML cells, which include suppression of nuclear translocation of NE-B, stimulation of leukemia self renewal via interaction with either of the Fit-1 or KDR VEGF receptors, and activation of the phosphoinositol-3-kinase/Akt signaling pathway. We propose that agents which modify cellular VEGF elaboration or VEGF receptor signaling will impair leukemia progenitor self renewal, lower resistance to maturation signals, impair generation of inflammatory cytokines, and promote more effective hematopoiesis in MDS. Our efforts to delineate the VEGF receptor signaling pathway in AML progenitors provides a unique opportunity to validate in vivo target inhibition as an endpoint for biologic activity of novel therapeutics. In this project, we will investigate three Specific Aims that evaluate novel therapeutics which inhibit the actions of VEGF or its receptor signaling in patients with MDS, and delineate the relationship between in vivo target inhibition, and biologic and hematologic endpoints. The Specific Aims of this proposal are: 1) To determine the biologic effects of the VEGF inhibitor, thalidomide, in patients with MDS, and the relationship between target inhibition and hematologic response. 2) To investigate the molecular and pharmacologic effects of the VEGF receptor tyrosine kinase inhibitor, SU-5416, in vitro and in animal models. 3)To determine the biological effects of SU-5416 in patients with MDS, and the relation between hematologic response and VEGF -receptor tyrosine kinase inhibition in clinical specimens.