This proposal is the Laboratory Program of a Breast Cancer Treatment Group, which is applying for funding through a COOPERATIVE AGREEMENT with the National Cancer Institute (RFA CA094-004). We have produced monoclonal antibodies (MAbs) against the EGF receptor which block its function in signal transduction and can prevent growth of tumors expressing the receptor, both in culture and in xenografts. Anti-HER2 MAbs from Genetech also have antitumor activity. We have demonstrated the capacity of combination treatment with antireceptor MAb plus chemotherapy to eliminate well-established human tumor xenografts. Our approach is novel in that it simultaneously attacks the breast cancer cell at two sites which appear to be critical to cell growth and survival: signal transduction pathways activated by essential growth factors, and DNA or cellular architectural elements (tubulin) that are susceptible to damage by the drugs most active against breast cancer. We anticipate that this 'double hit' approach will be a paradigm for other combination therapies, which can take advantage of the relative inability of malignant cells to handle insults that require regulation of growth at 'checkpoints' during repair of damage. We plan preclinical laboratory experiments to determine the optimal protocols for treating breast cancer patients with antireceptor MAbs plus chemotherapy. Both non-malignant 184 mammary epithelial cells and three breast cancer cell lines (MCF7, BT474, and MDA468) will be investigated, to obtain data on efficacy against low and high receptor expressors, and to explore possible selectivity in the toxicity of therapy. Scheduling and dosing of drug and antireceptor MAb will be major targets of studies in a series of experiments with cultures of breast cells, and against well- established nude mouse xenografts of breast cancer cells. The chemotherapeutic agents to be evaluated include those with strongest activity against human breast cancer. Initial studies have included doxorubicin, Taxol, and cisplatinum, cyclophosphamide and 5-fluorouracil will be added. The results of these preclinical experiments with anti EGF receptor MAbs will be translated directly into clinical trials in the paired Clinical Program of the COOPERATIVE AGREEMENT proposal. Results with anti-HER2 MAb will be incorporated into clinical trials by Genentech, Inc.
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