VIRGINIA UNIV CHARLOTTESVILLE CHARLOTTESVILLE United States
Breast cancer is a devastating disease that affects both women and men, and despite many advancements it is still often deadly and remains incurable when metastatic. Efficient novel treatments, or enhancements to current ones, are desperately needed to improve breast cancer therapy and to extend the lives of patients. Therefore, the overall goal of this proposal is to develop a tumor-specific, safe and effective therapy for breast cancer. We concentrate on HER2-overexpressing tumors, which are diagnosed in one in four patients. Currently HER2 targeted therapies achieve highest response rates when combined with chemotherapy, but chemotherapy causes undesirableside effects due to off-target effects on normal tissue, which diminishes quality of life for the patient. One way to address this problem is to use a drug that either attacks only tumor cells or enhances the response of tumors but not normal tissues to current therapies. During the first year of this project we demonstrated that so called low voltage activated LVA calcium channels are aberrantly expressed in HER2-positive breast cancer cell lines, in PyMT mouse tumors-derived cell lines, and contribute to worsen prognosis in human breast cancer patients analysis of publicly available data. We showed that inhibition of LVA channel with clinically approved agent mibefradil reduces oncogenic signaling and enhances anticancer activity of standard therapeutic agents. Similar, although not as pronounced, effects were observed in cell lines with down-regulated expression of LVA channel isoform CACNA1G. In summary, the results from the 1st year of this project provide foundation for future more extensive molecular studies in vitro, and efficacy studies in vivo.