) This proposal is the Laboratory Program of a Breast Cancer Treatment Group (J. Mendelsohn, Principal Investigator) which is applying for funding through a COOPERATIVE AGREEMENT with the National Cancer Institute (RFA CA-94-004). 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 Genentech 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. 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 cancer cells, and against well- evaluated 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; cyclophoslamide 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 this COOPERATIVE AGREEMENT proposal. Results with anti-HER3 Mab will be incorporated into clinical trials by Genetech, Inc. This proposal, the Clinical Program of a Breast Cancer Treatment Group (J. Mendelsohn, Principal Investigator), requests funding through a Cooperative Agreement with the National Cancer Institute (RFA-CA-94-004). We have produced monoclonal antibodies (Mabs), against the EGF receptor (EGFR), that block activation of receptor tyrosine kinase and inhibit the growth of tumors expressing the receptor. We consider these Mabs to be pharmacologic antagonists of receptor mediated signal transduction pathways, although they also may have the capacity to activate immune antitumor mechanisms. In a series of experiments in vivo we have observed that combined treatments with anti-EGFR Mabs plus either doxorubicin or paclitaxel have a major antitumor effect, resulting in the disappearance of well-established tumor xenografts that cannot be eradicated by any other known therapy. Human clinical trials with murine anti-EGFR Mabs, conducted by our group, have shown that the administration of single doses of the muMAbs is safe and that we can achieve plasma levels of the muMAb sufficient to saturate receptors. Based on these pre-clinical and clinical data we plan to conduct a series of Phase I and II clinical trials with the human: murine chimeric version of MAb 225 (HC MAb 225). Our goal is to determine the safety, feasibility, and noncomparative efficacy of multiple doses of MAb and of chemotherapy plus MAb in the treatment of patients with metastatic breast cancers expressing high levels of EGFR. The description of efficacy will be based on experience with patients who have received no prior chemotherapy for their advanced disease. Simultaneously, we will obtain pharmacokinetic data and tissue biopsies to study potential mechanisms of action Should these clinical trials demonstrate the safety, feasibility, and reasonable activity of these treatments, we plan to design prospective, randomized trials of chemotherapy with and without MAb, in order to determine the comparative efficacy of the combination. Such randomized comparisons cannot proceed in the absence of the research proposed in this application.
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