Targeting DAMP-Induced Inflammation to Prevent Metastasis
Abstract
The vast majority of deaths (~90%) due to breast cancer occur because the cancer spreads from its primary location to distant sites through a process called metastasis. This study will evaluate a novel approach to combat metastasis by controlling the inflammatory process that cancer cells utilize to spread through the body. Debris released from dead and dying cancer cells or normal cells near a tumor can recruit and activate inflammatory cells to the site of the tumor because the immune system believes such cellular debris was created by an infection. This acute inflammatory response is normally desirable and resolves once infections are cleared. However, increasing evidence indicates that cancer cells hijack and convert this acute inflammatory response into a prolonged response to facilitate cancer spread to distant sites in the body. Key cellular initiators of this debris-induced response are cellular DNA and RNA, molecules that are usually not seen outside of cells. When cellular DNA is released from cells, they activate an initial, non-specific immune response and recruit inflammatory cells to locations where such debris is present. In this project, we propose to explore the use of novel therapeutic agents that can act as molecular scavengers to pick up such cellular DNA debris and inhibit its ability to initiate non-specific inflammatory responses. Our preliminary results from mouse studies lead us to believe that this approach will greatly limit activation of such responses and thereby limit metastasis of breast cancer cells. If successful, we believe that this approach will become a novel means to control the spread of breast cancer in patients and dramatically reduce the number of women who die from metastatic disease. Which overarching challenge(s) does this research address? This proposal addresses the following overarching challenge, "Eliminate the mortality associated with metastatic breast cancer." As outlined in the Breast Cancer Research Program breast cancer landscape, "Approximately 90% of deaths due to breast cancer are a consequence of metastatic disease. Treatments to permanently eradicate metastasis do not exist." Therefore, preventing metastasis is a critical clinical need. What types of patients will it help and how will it help them? This research is geared toward helping all women with breast cancer where limiting cancer metastasis is expected to reduce morbidity and improve their overall survival. What are the potential clinical applications, benefits, and risks? Clinical applications would include women newly diagnosed with breast cancer as well as ones who have undergone surgical treatment to remove the primary tumor. If successful, the benefits would be that we would expect to slow or halt spread of the cancer to distant sites in the body. What is the projected time it may take to achieve a patient-related outcome? We hope to start a clinical study in women with breast cancer in approximately 5 years assuming this proposal is supported. We are actively working on the preclinical development of such nucleic acid scavengers for a number of clinical settings but believe that our novel approach could make a major impact in the setting of metastatic breast cancer and would like to focus our efforts in this direction. What is the likely impact of this study on ending breast cancer? If successful, we anticipate that by ending breast cancer metastasis, this approach would result in a ~90% reduction in mortality from breast cancer, assuming that the primary tumor can be safely and effectively removed.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610512
Entities
People
- Smita K Nair
Organizations
- Duke University
- United States Army