Targeting Neutrophil Protease-Mediated Degradation of Tsp-1 to Induce Metastatic Dormancy
Abstract
Breast cancer affects more than 1.7 million individuals a year worldwide, with approximately 500,000 deaths. In the United States, over 230,000 are diagnosed resulting in 40,000 deaths annually. Importantly, >90% of this mortality is a consequence of metastatic disease that is resistant to adjuvant therapies. As a consequence, an estimated 155,000 Americans are currently living with metastatic breast cancer (ASCO post 2014). Despite this clinical significance, there is a conspicuous lack of a single Food and Drug Administration-approved molecularly targeted anti-metastatic therapy. Given the unmet medical need, our goal is to develop anti-metastatic therapeutic approaches for effective treatment. We are proposing that breast cancer patients who present inflammation in the lungs (cigarette smoke, bacterial infection, COPD/emphysema-related) have an increased potential for developing lung metastasis. Using mouse models, we have recently shown that external inflammation in the lungs is associated with increased incidence of metastasis. We show that the inflamed lungs exhibit a dramatic increase in neutrophils. These neutrophils carry discrete granules, which are bags with specific cargos. In the inflamed lungs, the neutrophils undergo degranulation and spill the cargos into the lung microenvironment. We have discovered that one of the cargos is comprised of two key serine proteases, Cathepsin G (CG) and neutrophil elastase (NE). These proteases have the capacity to degrade Thrombospondin-1 (Tsp-1), a major suppressor of cancer in the normal lung. Hence, NE/CG-mediated destruction of Tsp-1 generates tumor-promoting conditions. As a consequence, disseminated tumor cells are able to exploit these conditions and grow out into lethal macrometastasis. We hypothesize that intervention against inflammation-driven NE/CG- Tsp-1 axis can be developed into an anti-metastatic therapy in breast cancer. Using a combination of genetic and pharmacological approaches, we propose to achieve the following objectives: (1) to establish that the neutrophil NE/CG-Tsp-1 axis is the dominant pathway in inflammation-mediated metastasis, (2) to determine the molecular mechanisms by which neutrophil CG/NE-Tsp-1 axis promotes metastasis, (3) to show that NE/CG-Tsp-1 axis modulates Tsp-1-mediated metastatic dormancy, (4) to assess whether pharmacological inhibition of CG/NE with Sivelestat can be used to inhibit metastasis, and (5) to determine if induction of Tsp-1 expression in the lung microenvironment with a novel DWLPK peptide constitutes an anti-metastatic approach. The preclinical data obtained from these studies will generate unique translational opportunities and may lead to the design of future clinical trials for breast cancer patients that exhibit pulmonary inflammation (cigarette smoke, COPD/emphysema-related). Notably, the dual NE/CG protease inhibitor Sivelestat is available and is currently being used in Phase III clinical trials of acute lung injury with systemic inflammatory response syndrome. We expect that findings from our studies will support the potential for repurposing Sivelestat as a dual protease antagonist in the treatment of metastasis in breast cancer patients with lung inflammation. Similarly, induction of Tsp-1 expression with a novel DWLPK peptide drug either alone or in combination with Sivelestat has tremendous potential for designing future clinical trials for high-risk breast cancer patients. This project addresses Breast Cancer Research Program overarching challenges of revolutionizing treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective and advancing the field towards the elimination of mortality associated with metastasis in high-risk breast cancer patients. It also addresses metastatic dormancy and progression of breast cancer to life-threatening metastasis. In summary, we anticipate that the proposed studies will lead to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610615
Entities
People
- Vivek Mittal
Organizations
- United States Army
- Weill Cornell Medicine