HMGB1 and Its Isoforms as Biomarkers for Mineral Fiber Exposure and MM Detection
Abstract
Topic and Relevance Area: Gaps in screening, early detection and diagnosis for malignant mesothelioma (MM). The Problem: MM is a cancer caused by exposure to asbestos. Asbestos fibers that are inhaled through the mouth and nose may eventually become embedded in the lining of the lungs, causing harmful inflammation of the pleura and resulting in mesothelioma or asbestosis (scar tissue formation in the lungs). Most patients with mesothelioma die as a result of respiratory failure or pneumonia. Some patients develop a small-bowel obstruction when the tumor extends through the diaphragm. A smaller number die of cardiac complications when the tumor invades the pericardium, the thin membrane that surrounds the heart, and the heart itself. MM is most often diagnosed in the later stages of disease when it is advanced or malignant, and current gold standards for therapy only extend survival by an average of about 11 weeks. Early MM detection is associated with better responses to therapy and prolonged survival. In the United States, about 25 million people have potentially been exposed to asbestos, and it is unknown how many more have been exposed to the carcinogenic fiber erionite or are at risk for developing MM because they carry BAP1 mutations. It is not feasible to monitor such a large population for the development of MM with the current screening technologies. A biomarker of exposure would help to identify those individuals who have been exposed to dangerous levels of mineral fibers and are at increased risk of MM. No biomarkers of exposure are currently available. A biomarker for MM would help identify MM at an early stage, when it is susceptible to therapy. Candidate biomarkers for MM have been proposed, such as soluble mesothelin-related peptides, osteopontin, and fibulin-3. However, each is limited by sensitivity, specificity, or reproducibility. Thus, the need to identify biomarkers for mineral fiber exposure and for MM remains. Scientific Objectives and Rationale: Our group has identified how asbestos damages mesothelial cells and what proteins are responsible for the survival of the damaged cells that accumulate genetic mutations and become cancerous. We have shown that a protein called HMGB1 kick-starts an inflammatory reaction that leads to the survival of asbestos-damaged mesothelial cells. However, due to lack of animal models, we, and others, have not been able to conclusively prove the involvement of HMGB1 in MM development and progression. As a part of this proposal, we will develop the required animal models that will significantly enhance our knowledge of how MM develops, elucidate which isoform of HMGB1 is required at what stages of disease, and prospectively evaluate HMGB1 and its isoforms as novel biomarkers to distinguish between asbestos exposure and MM. Military Benefit/Relevance: Veterans who served in any of the following occupations may have been exposed to asbestos: mining, milling, shipyard work, insulation work, demolition of old buildings, carpentry and construction, manufacturing and installation of products such as flooring and roofing. Over 300 products such as valves, brakes, gaskets, cements, adhesives, and pipe coverings containing asbestos were used by the military. Families of Veterans may also have been significantly exposed through inhalation of residual fibers on the clothes of the Service personnel. More recently, Veterans who served in Iraq and other countries in that region could have been exposed to asbestos when older buildings were damaged and the contaminant released into the air. Symptoms of asbestos-related diseases, such as shortness of breath, coughing, and chest pain, often do not appear until 20 to 50 years after the exposure. Clinical Application and Impact: Our goal is to develop and validate a clinically usable blood-based assay for early detection of MM. A biomarker for mineral fiber exposure would allow us to identify those individ
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610441
Entities
People
- Michele Carbone
Organizations
- Mauna Kea Observatories
- United States Army