Virtually all drugs targeting tumor neovascularization that are being tested clinically can be classified as anti- angiogenic agents. These agents are generally cytostatic, inhibiting only new blood vessels undergoing proliferation, migration, or tube formation, and sparing established vessels. An alternative approach for targeting tumor vessels involves the use of vascular targeting agents. These agents are inherently cytotoxic, and ideally target all vessels within the tumor, both new and established. Since these compounds are cytotoxic, it is important to target only tumor endothelium, so that normal endothelium are spared. Therefore, a more detailed understanding of the molecules that are most differentially and abundantly expressed on tumor vessels is needed to facilitate the efficient clinical development of vascular targeting agents. We hypothesize that breast tumor endothelium are qualitatively different in their gene expression patterns from normal breast endothelium. Our objective is to obtain molecular profiles of breast tumor endothelium and compare the gene expression patterns to normal breast endothelium. We will employ our novel method for laser capture microdissection of endothelial cells from both human and mouse breast tumors and human and mouse normal breast tissue. We will extract and amplify the RNA, and proceed with genomic profiling using 44k long oligo-spotted microarrays. We will embark on a genome-wide screen for changes in gene expression between endothelium from breast tumors and normal breast tissue, and between luminal and basal subtypes of tumors. We will also compare gene expression profiles between mouse and human endothelium. We will validate the differential expression of tumor endothelial markers using real'time PCR, and use in situ hybridization or existing antibodies to localize transcripts or gene products as being derived from tumor endothelium. Finally, we will see if there is a change in protein expression of tumor endothelial markers in a human clinical trial for patients with metastatic breast cancer treated with the angiogenesis inhibitor 2-methoxyestradiol and paclitaxel. A more detailed understanding of the molecules that are most differentially and abundantly expressed on breast tumor vessels may facilitate the efficient clinical development of vascular targeting agents for breast cancer, and for developing diagnostic markers to serve as surrogate markers for response to anti-angiogenic therapy.
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