Enhancing Immunotherapy for Triple-Negative and HER2+ Breast Cancer Using EpCAM Aptamer-siRNA-Mediated Gene Knockdown
Abstract
Although treatment for breast cancer has dramatically advanced in the past decade, it remains the most commonly diagnosed cancer and the second-leading cause of cancer death among US women. I have seen many women suffer from breast cancer, struggling with tumor relapse and metastasis. Working in cancer immunology and immunotherapy research as a female scientist, I feel an obligation to participate in the fight to cure breast cancer. I believe cancer immunotherapy, which has achieved great success in recent years for other tumors, offers a promising approach to cure breast cancer. My career goal is to become an independent investigator in breast cancer research at a world-class institute, leading my own laboratory to help save the lives of cancer patients. In Dr. Lieberman?s lab, I am acquiring cutting edge skills and invaluable experience in designing breast cancer immunotherapy, including the use of cell lines, mouse models, and the design and evaluation of targeted nucleic acid therapeutics. The rich immunology research environment at Boston Children?s Hospital and Harvard Medical School, with many collaboration and learning opportunities, has offered me a new outlook on breast cancer research and novel ideas for development of immunotherapeutic strategies. My proposed research aims to investigate novel approaches to modify breast cancer cells to make them immune targets. This project will allow me to deepen my understanding of cancer immunology and breast cancer research. Cancer immunotherapy takes advantage of the patient?s own immune system to kill malignant tumor cells. It requires that tumor cells be visible to the immune system through their expression of tumor-specific molecules, called antigens. As many breast cancer cells are not well recognized by the immune system, current immunotherapy using checkpoint inhibitors is predicted to have poor efficacy for most aggressive breast cancers. One goal of my project is to manipulate breast cancer cells to express tumor antigens that could be recognized by immune cells. Many of the immune killer lymphocytes that infiltrate and recognize a tumor and could potentially kill tumor cells, are functionally impaired. Another aim is to improve the ability of tumor-infiltrating immune cells to attack and kill tumor cells. I plan to achieve these goals by utilizing a novel drug platform, which links a targeting molecule that recognizes a receptor only highly expressed on cancer cells to a small nucleic acid that selectively inhibits the expression of one gene at a time. This efficient platform has the potential to selectively target breast cancer cells, making them susceptible to tumor-killing lymphocytes and better at stimulating an antitumor immune response. I will design and optimize these targeted drugs and evaluate their ability to enhance tumor immune responses and control tumor growth either alone or in combination with each other or with other immunotherapeutic approaches. I will also investigate how the immune system is activated by these novel drugs. My research will evaluate the enormous potential of this novel drug platform for revitalizing immunotherapeutic efficacy for patients with poor prognosis breast cancers including, but not limited to, triple-negative and HER2+ breast cancers. I am optimistic that these novel targeted drugs, with their small size and high selectivity, have great potential to improve treatment efficacy and lower toxicity for breast cancer patients compared to currently used drugs such as antibodies that act as checkpoint inhibitors. There is a good chance to apply the knowledge I acquire from this project to the clinic. These nucleic acid-based drugs can be readily designed and synthesized. If they achieve marked tumor regression in preclinical studies, as I expect, I believe they could enter clinical trials within 3 to 4 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910039
Entities
People
- Ying Zhang
Organizations
- United States Army