Growth factors and their cell surface receptors are crucial for cell growth regulation. One or more erb B proto-oncogenes encoding EGF, HER-2 and HER-3 receptors are amplified and/or overexpressed in about two- thirds of human breast cancers. Overexpression of HER-2 receptor in human breast and ovarian cancer correlates with poor outcome and may predict response to chemotherapy in the clinic. A growth-regulatory circuit involving HER-2/neu receptor and autocrine/paracrine activation by heregulin, a newly-purified ligand, is postulated to advance malignancy. Monoclonal antibodies that bind HER-2 receptors exert a cytostatic effect in suppressing growth of cells with HER-2 overexpression. New laboratory work suggests that activation of HER-2/neu receptors by antireceptor antibody enhances cellular sensitivity to drugs that -damage DNA- and, thereby, maximizes tumor cell killing. Models of human breast and ovarian cancers with and without overexpression of HER-2 receptors or heregulin have been established in our laboratory and will be used to study:

* Anticancer effects of a new humanized monoclonal antibody to HER-2/neu receptor alone and in combination with chemotherapeutic drugs (cisplatin and alkylators) that damage cellular DNA. Preclinical data will be collected on efficacy and treatment schedules for a humanized antibody to HER-2 receptor designed for use in clinical trials. The postulated therapeutic advantage of combined therapy with antireceptor antibody and cytotoxic drugs will be tested, with aims to optimize in vivo conditions for maximal cytocidal effects. This data-is required to continue ongoing clinical trials with these agents.

* Clinical significance of HER-2/neu receptor or heregulin gene expression in drug resistance. To test the role of HER-2 gene in genesis of chemotherapy resistance, parental cells with single-copy, low expression of HER-2 gene and molecularly-engineered daughter cells with multi-copy, high expression of HER-2 gene will be compared for relative drug sensitivity. Tumor cells engineered for overexpression of heregulin will also be used to test effects of autocrine/paracrine activation of HER-2 on drug sensitivity.

* Modulation of DNA repair in synergistic antitumor effects of antireceptor antibody and cisplatin. Measure of the formation and repair of cisplatin-DNA adducts and unscheduled DNA synthesis will be done to test the hypothesis that DNA repair pathways are altered by growth factor receptor signaling pathways. Effects of ligand or receptor overexpression and of antireceptor antibody will be compared.

This basic and translational research approach is aimed toward continuation and support of clinical trials of a novel treatment option in breast and ovarian cancer. New knowledge on biologic actions of heregulin and HER-2 receptors will be applied toward new strategies to target and exploit overexpressed growth factor receptors at the surfaces of malignant cells.

R29CA060835

1995-02-01

2000-01-31