Abstract
Malignant pleural mesothelioma (MPM) tumors are remarkably aggressive and most patients only survive for 5–12 months; irrespective of stage; after primary symptoms appear. Compounding matters is that MPM remains unresponsive to conventional standards of care; including radiation and chemotherapy. Currently; instead of relying on molecular signatures and histological typing; MPM treatment options are guided by clinical stage and patient characteristics because the mechanism of carcinogenesis has not been fully elucidated; although about 80% of cases can be linked to asbestos exposure. Several molecular pathways have been implicated in the MPM tumor microenvironment; such as angiogenesis; apoptosis; cell-cycle regulation and several growth factor-related pathways predicted to be amenable to therapeutic intervention. Furthermore, the availability of genomic data has improved our understanding of the pathobiology of MPM. The MPM genomic landscape is dominated by inactivating mutations in several tumor suppressor genes; such as CDKN2A; BAP1 and NF2. Given the complex heterogeneity of the tumor microenvironment in MPM; a better understanding of the interplay between stromal; endothelial and immune cells at the molecular level is required; to chaperone the development of improved personalized therapeutics. Many recent advances at the molecular level have been reported and several exciting new treatment options are under investigation. Here; we review the challenges and the most up-to-date biological advances in MPM pertaining to the molecular pathways implicated; progress at the genomic level; immunological progression of this fatal disease; and its link with developmental cell pathways; with an emphasis on prognostic and therapeutic treatment strategies.
Highlights
Malignant mesothelioma is an aggressive and universally lethal cancer that arises because of pathological transformations in the mesothelium, a protective serous membrane that lines several organs in the body, such as the lungs, the intestines, the heart and tunica vaginalis
malignant pleural mesothelioma (MPM) is classified as a rare disease and an estimated 3000 cases are diagnosed in the United States each year, the incidence is expected to remain steady, or rise, until 2055, because of the developmental latency of the disease; correspondingly, two thirds of mesothelioma cases are diagnosed in patients over the age of 65 [1]
A clinical trial was launched to investigate the efficacy of vatalanib, a dual pan-VEGFR and platelet derived growth factor receptor (PDGFR)-β inhibitor in mesothelioma, and the results showed minimal benefits, its low toxicity could warrant further experimentation to explore synergistic effects if combined with other standard treatments [16]
Summary
Malignant mesothelioma is an aggressive and universally lethal cancer that arises because of pathological transformations in the mesothelium, a protective serous membrane that lines several organs in the body, such as the lungs (pleural), the intestines (peritoneum), the heart (pericardium) and tunica vaginalis. Whereas patients diagnosed with epithelioid mesothelioma reportedly survive the longest (12–27 months), the appropriate course of treatment can be onerous to determine [8]. This is due to the inherent tumor heterogeneity and the difficulty in staging the disease, which underscores the need to better understand the disease pathobiology at the molecular level. We discuss current advances in mesothelioma biology and heterogeneity in the tumor microenvironment, starting with heterogeneity at (1) the molecular pathway level, followed by progress at (2) the genomic level, (3) immunological progression of MPM, and the link with (4) developmental/stem cell pathways associated with the disease. Our focus is to discuss promising new therapeutic strategies under investigative development, which could potentially permit a longer and better quality of life for those with mesothelioma
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