Low-Voltage Activated Calcium Channels - Their Role in HER2-Driven Breast Cancer and Potential as a New Therapeutic Target
Abstract
Breast cancer is a devastating disease affecting both women and men, and despite many advancements, it remains incurable when metastatic. Efficient novel treatments, or enhancements to current ones, are desperately needed to improve breast cancer therapy and extend patient lives. The overall goal of this proposal is to develop tumor-specific, safe, and effective therapy for breast cancer. We will concentrate on HER2-overexpressing tumors, which are diagnosed in one in four patients. Despite enormous progress in developing targeted therapies, such as the anti-HER2 antibodies, cancer cells eventually acquire resistance, which clinically is manifested by tumor growth/recurrence in spite of targeted therapy. Currently HER2-targeted therapies achieve highest response rates when combined with chemotherapy, but chemotherapy causes undesirable side effects due to off-target effects on normal tissue, which diminishes quality of life for the patient. A 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. Such an approach enables the use of smaller doses to treat the tumor, resulting in fewer side effects. Our research shows that so-called low voltage activated (LVA) calcium channels are aberrantly expressed in breast cancer cells, most notably in HER2-positive tumors. We propose to investigate how expression of LVA calcium channels may promote cancer cell growth and progression and confer resistance to therapy. We will further investigate whether LVA channel inhibitors, mibefradil and similar drugs, can be employed to treat an advanced HER2-positive breast cancer. Our proposed research is expected to reveal an important mechanism(s) that supports the progression of HER2+ breast cancer. The successful outcome of this project will advance the rational approach to develop a new generation of anticancer agents for the treatment of patients suffering from advanced breast tumors. Since specific LVA calcium channel inhibitors are already available, relatively safe, and Food and Drug Administration-approved for hypertension and related conditions, we believe that our studies could progress quickly into clinical trials. Importantly, mibefradil, a LVA channels inhibitor that will be used extensively in our studies, is already undergoing clinical trials in brain tumor patients and is considered for treatment of other types of cancer. Successful accomplishment of the goals of this 3-year study, together with positive outcomes from the clinical trials mentioned above, could quickly (3- to 5-year time frame) lead to the breast cancer-specific clinical trials and to the development of a novel, safe, and efficient therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510308
Entities
People
- Jaroslaw Dziegielewski
Organizations
- United States Army
- University of Virginia