TGFbeta Type I Receptor Kinase Inhibitors - A Novel Treatment for Breast Cancer
Annual rept. 1 Jun 2000-31 Mar 2001
CANCER INST OF NEW JERSEY PISCATAWAY
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Transforming Growth Factor-Bs TGFBetaare 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 TGFBeta on normal tissue stroma, bloodvessels and immune cells could be developed as a novel approach to the treatment of breast cancer. We propose to block TGFBeta action by developing small molecules that inhibit the type I TGFBeta receptor kinase, which is the key molecule that initiates and mediates TGFBeta signaling. We plan to develop a cell free ELISA-type assay for high-throughput screening for selective inhibitors of TBR-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 TBR-I kinase. These will then be tested against normal cells in vitro using a number of different assays for TGFBetas biological effects. Promising compounds will then be tested for their antitumor activity against highly metastatic, - angiogenic and immunogenic varieties of transplantable breast cancers in mice.
- Medicine and Medical Research