TGF-beta Type I Receptor Kinase Inhibitors - A Novel Treatment for Breast Cancer
Annual summary rept. 1 Jun 2002-31 May 2003
CANCER INST OF NEW JERSEY NEW BRUNSWICK
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Transforming Growth Factor-beta TGF-beta are polypeptides that are constitutively secreted and activated by many breast carcinomas. They contribute to the tumors ability to invade and metastasize, to induce angiogenesis and to escape from immune destruction. These circumstances raise the question whether blocking the effects of tumor-derived TGF-beta on normal tissue stroma, blood vessels and immune cells could be developed as a novel approach to the treatment of breast cancer. We propose to block TGF-beta action by developing small molecules that inhibit the type I TGF-beta receptor kinase, which is the key molecule that initiates and mediates TGF-beta signaling. We plan to develop a cell free ELISA-type assay for high-throughput screening for selective inhibitors of T beta R-I kinase activity by using an antibody that specifically detects the phosphorylated form of its substrate, Smad2. Combinatorial libraries of small molecules will then be screened for potent and highly selective for the T beta R-I kinase. These will then be tested against normal cells in vitro using a number of different assays for TGF-betas biological effects. Promising compounds will then be tested for their antitumor activity against highly metastatic, - anqioqenic and immunoqenic varieties of transplantable breast cancers in mice.
- Medicine and Medical Research