Malignant pleural mesothelioma (MPM) is a highly aggressive form of cancer that develops within the pleural lining of the lungs. The primary cause MPM is the inhalation of microscopic asbestos fibers. Once inhaled, these fibers become lodged in the lining of the lungs where they accumulate and cause cellular and genetic damage that can ultimately result in the development of cancer. MPM is the most common variant of mesothelioma, accounting for around 75% of cases in the U.S., and may take anywhere from 10 to 50 years to develop. MPM is most commonly traced to occupational exposure; persons at high risk for MPM include workers in factories, construction sites, and shipyards.
Asbestos-related malignancies were a major public health problem prior to the removal of asbestos from naval ship construction. However, older naval vessels and military facilities containing asbestos were in use long after it was removed from U.S. manufacturing, resulting in thousands of Veterans, and their dependents, suffering asbestos exposure throughout the 1940s to the 1970s and even later in some cases. With the latency period for MPM development spanning potentially decades, all of these Veterans, and their families, remain at risk for this disease. Indeed, it is estimated that military Veterans account for one-third of all MPM patients due to the close quarters in naval vessels and older military barracks. Despite this estimation, there is little or no data on the phenotype of military exposure and MPM pathogenesis. This proposal seeks to address this knowledge gap regarding military-related mesothelioma, one of the key Focus Areas of the Fiscal Year 2016 Peer Reviewed Cancer Research Program.
Given the unique working environment and conditions of military personnel compared to the civilian population, it is likely the genomic mechanisms governing MPM differs between these two groups. The overall objective of this proposal is to refine the classification of MPM into biologically and prognostically distinct subgroups, relate these subgroups to the military-exposed Veterans, and rationally design potential biomarker-selected targeted therapies for the military/Veteran population for future human trials. Our research group has defined the mutational landscape of MPM and has identified the most commonly mutated genes of the disease. We have also classified MPM into four distinct molecular clusters that provide new opportunities to identify MPM patients with better prognosis as well as to rationally divide tumors based on distinct molecular/biochemical driving mechanisms. For this proposal, we genetically test tumors for the five most frequently mutated genes in MPM from cohorts of both civilian and Veteran MPM patients from the Norfolk, VA and Boston, MA areas. We will then establish the distribution of these mutations of all types in the four molecular cluster groups that we have classified. Frequently observed mutations or other genomic aberrations in these populations will be further interrogated using genetically engineered mouse models (GEMMs) to more completely understand MPM carcinogenesis and progression, as well as to identify potential targets for therapy. Finally, we will develop in vivo PDX models from the diagnostic/prognostic biomarkers that are identified in the civilian and military populations to focus preclinical therapeutics on the two extreme subtypes of MPM: 1 and 4. The results obtained from these studies will inform the design of future early phase treatment trials evaluating novel biomarker-driven targeted therapies for MPM in the military/Veteran population. The results obtained from the work in this proposal will be relevant to thousands of military Veterans who were exposed to asbestos during performance of their duty, as well as their families who likely suffered exposure to asbestos as well. The identification of particular genomic signatures specific to military personnel will lead to better diagnosis and earlier detection of MPM in this patient population and lead to improved survival among Veterans afflicted with this disease.