Identification and Targeting of Metastasis-Suppressing miRNAs in Triple-Negative Breast Cancer
Abstract
Over 200,000 new cases of invasive breast cancer are diagnosed in the United States each year and account for approximately 40,000 deaths. Importantly, almost all the deaths are due to widespread metastatic disease. A subset of advanced high-risk breast cancer patients already present pronounced metastatic lesions at the time of initial diagnosis of cancer. These advanced-stage patients are particularly difficult to treat and therefore have a 5-year survival rate of only 22%. In addition, many breast cancer patients who were previously treated eventually exhibit metastatic recurrence. Despite this clinical significance, there is a conspicuous lack of a single Food and Drug Administration-approved molecularly targeted therapy for the treatment of breast cancer metastasis. Thus, therapies that specifically target cancer cells, regress existing metastases, and have fewer debilitating side effects are desperately needed. One promising new idea for treatment is "microRNA (miRNA) replacement therapy." miRNAs are small RNA molecules that occur naturally in our normal cells and regulate many different cellular functions. In cancer cells, their expression is frequently altered, thus changing the biology and behavior of the cancer cells. Previously, we have shown that miRNA-708 is abundant in primary breast tumors but is completely suppressed in breast cancer cells that have metastasized to the lungs. Importantly, introducing miR-708 back blocked metastasis. In this proposal, we aim to study a panel of miRNAs that we have identified and determine their potential as novel drugs in eliminating pre-existing metastases. We will investigate a novel way of delivering the identified miRNAs to cancer cells in mouse models of metastatic breast cancer in such a way that results in elimination of the metastatic lesions with limited side effects. Specifically, we aim to address the following: (1) Identify miRNA molecules that can eliminate the lung, brain, or bone metastatic lesions that form in late-stage breast cancer patients. (2) Use a novel delivery method ("DNAsomes") to administer therapeutic miRNAs of interest to mouse models of breast cancer in order to eliminate metastatic lesions. The research proposed in this application has a high likelihood of impacting clinical treatment of metastatic breast cancer by addressing two important overarching challenges in breast cancer research: (1) eliminating the mortality associated with metastatic breast cancer and (2) revolutionizing treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective. The proposed work will most greatly benefit the 20%-25% of breast cancer patients diagnosed with triple-negative breast cancer (TNBC), which is the most aggressive form of breast cancer, as well as other types of metastatic breast cancer. African-American women, who are twice as likely to develop TNBC compared to Caucasian American women, will benefit greatly. Furthermore, successful delivery of the miRNAs via DNAsomes will be applicable to any cancer or disease where miRNA replacement therapy would be beneficial. The preclinical data that would emerge from this study can be expanded into investigational new drug (IND) enabling studies. We expect that that IND enabling studies will take 3 years, and the approximate time for these therapeutics to move into clinical trials will be approximately 5-10 years. Because metastasis accounts for the majority of breast cancer mortality, this work has a high likelihood of dramatically reducing and almost eliminating mortality due to breast cancer. Overall, this body of work could lead to the development of new effective therapeutics, thus providing a much needed viable option for patients diagnosed with late-stage metastatic breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610065
Entities
People
- Lauren Havel
Organizations
- United States Army
- Weill Cornell Medicine