Egf Receptor Mabs and Chemotherapy/Characterization of Synergistic Interactions Between Cyrotoxic Agents and Inhibitors of the Tyrosine Kinase Growth Factor Receptor Signaling Cascade

摘要

The focus of the laboratory and correlative science projects funded by this grant derive from the observation that antibodies directed against the EGFR receptor (225) and HER2 tyrosine kinase (4D5, trastuzumab) are effective in treating breast cancer in preclinical models. In the case of trastuzumab, these data have been extended to the treatment of human disease. Furthermore, Baselga and Mendelsohn and others have shown that inhibition of these tyrosine kinases with antireceptor antibodies augments the activity of a variety of cytotoxic agents. These results have been validated in large, prospective clinical trials, in which trastuzumab has meaningfully improved survival for patients with HER2/ neu overexpressing metastatic breast cancer when combined with paclitaxel or doxorubicin + cyclophosphamide. This report describes that drugs that inhibit other elements in the HER-kinase signaling pathway also inhibit breast cancer cells, and determines whether such inhibitors synergize with taxanes, to better elucidate the function of HER2 in breast cancer. Our investigation of the immunophenotypic characterization of human breast cancers for molecular markers thought to be potential correlates of the antitumor activity of taxanes, examining HER2 among other candidates, is similarly relevant to optimizing and individualizing anti-cancer treatment.