Military Exposure-Related Pleural Mesothelioma: An Innovative Translational Approach to Inform Novel Molecular-Targeted Treatment Development
Abstract
Malignant pleural mesothelioma (MPM) is a highly aggressive form of cancer that develops within the pleural lining of the lungs. Asbestos-related malignancies dropped precipitously in military/veteran populations upon the removal of asbestos from naval ship construction. However, older naval vessels and military facilities still containing asbestos were still in use decades later, resulting in thousands of veterans suffering asbestos exposure. Indeed, it is estimated that military veterans account for one third of all MPM patients. Despite this estimation, there is little data on the phenotype of military exposure and MPM pathogenesis. During this funding cycle, we demonstrated at the molecular level, Clusters 2 and 3 represented a continuum, or "histomolecular gradient", predominantly biphasic and sarcomatoid tumors, respectively. Correlated with the epithelial to mesenchymal transformation (EMT) process, the two more extreme clusters 1 and 4 were enriched for epithelioid and sarcomatoid tumors, respectively. We identified an association of single pattern cytoplasmic staining with markers of EMT, suggesting a complex role for BAP1 in MPM. In fact, it appears that military exposed MPM patients have a unique phenotype compared to matched civilian cohort (unpublished data undergoing secondary validation). We successfully generated conditional mouse lines with NF2, CDKN2a and p53 deletions in mesothelial cells (WT1-CreER driver) as single and multiple knockout mice. The mice were sacrificed 1 year after administration of tamoxifen with successful pleural MPM tumor generation in all genotypes. The final aim of this funding cycle was accomplished with establishment of patient-derived xenografts (PDX) from 14 patients (including 2 rare sarcomatoid tumors and several biphasic tumors) utilizing modifications of existing techniques such that it should be possible to created immortalized tumors from most patients with triplicate implantation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2022
- Accession Number
- AD1203260
Entities
People
- David Harpole
- Mary-beth Joshi
- Raphael Bueno
Organizations
- Duke University Hospital