Special Issue on Mechanisms of Mesothelioma Heterogeneity: Highlights and Open Questions

Felley‐Bosco, Emanuela

doi:10.3390/ijms19113560

Cited by 5 publications

(2 citation statements)

References 27 publications

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“…One limitation to the current study is that only a single MPM cell line was used for in vivo studies. As MPM is a heterogenous disease (60), future studies involving other mesothelioma cell lines or models may further delineate and expand on this possibility.…”

Section: Discussionmentioning

confidence: 99%

When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?

et al. 2019

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Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON) signaling axis is active in MPM. Targeting this pathway with a small molecule inhibitor, LCRF-0004, resulted in decreased proliferation with a concomitant increase in apoptosis. Cell cycle progression was also affected. Recombinant MST1 treatment was unable to overcome the effect of LCRF-0004 in terms of either proliferation or apoptosis. Subsequently, the effect of an additional small molecular inhibitor, BMS-777607 (which targets MST1R (RON), MET, Tyro3, and Axl) also resulted in a decreased proliferative capacity of MPM cells. In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis. Additionally, elevated expression levels of MST1 also correlated with better survival. This study also determined the efficacy of LCRF-0004 and BMS-777607 in xenograft MPM models. Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy in vitro , however BMS-777607 was far superior to LCRF-0004. The in vivo and in vitro data generated by this study indicates that a multi-TKI, targeting the MST1R/MET/TAM signaling pathways, may provide a more effective therapeutic strategy for the treatment of MPM as opposed to targeting MST1R alone.

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Section: Discussionmentioning

confidence: 99%

When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?

et al. 2019

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“…Instead, loss-of-heterozygosity (LOH) analysis demonstrated that the two areas of the chromosome most frequently altered in MPM are CDKN2A-ARF at 9p21, and NF2 at 22q12 [5,49,50]. CDKN2A encodes for a cell-cycle regulator mutated in more common cancers like melanoma, and neurofibromatosis 2 (NF2) acts as tumor suppressor that is part of the NF2/Merlin complex that makes up the NF2/Hippo pathway [51,52]. Deletions of 3p21 region, enclosing BAP1 gene are also reported in 33 MPM bioptic samples [53].…”

Section: Genetic Aspectsmentioning

confidence: 99%

Malignant Pleural Mesothelioma: Genetic and Microenviromental Heterogeneity as an Unexpected Reading Frame and Therapeutic Challenge

Abbott

Bortolotto

Benvenuti

et al. 2020

Cancers

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Mesothelioma is a malignancy of serosal membranes including the peritoneum, pleura, pericardium and the tunica vaginalis of the testes. Malignant mesothelioma (MM) is a rare disease with a global incidence in countries like Italy of about 1.15 per 100,000 inhabitants. Malignant Pleural Mesothelioma (MPM) is the most common form of mesothelioma, accounting for approximately 80% of disease. Although rare in the global population, mesothelioma is linked to industrial pollutants and mineral fiber exposure, with approximately 80% of cases linked to asbestos. Due to the persistent asbestos exposure in many countries, a worldwide progressive increase in MPM incidence is expected for the current and coming years. The tumor grows in a loco-regional pattern, spreading from the parietal to the visceral pleura and invading the surrounding structures that induce the clinical picture of pleural effusion, pain and dyspnea. Distant spreading and metastasis are rarely observed, and most patients die from the burden of the primary tumor. Currently, there are no effective treatments for MPM, and the prognosis is invariably poor. Some studies average the prognosis to be roughly one-year after diagnosis. The uniquely poor mutational landscape which characterizes MPM appears to derive from a selective pressure operated by the environment; thus, inflammation and immune response emerge as key players in driving MPM progression and represent promising therapeutic targets. Here we recapitulate current knowledge on MPM with focus on the emerging network between genetic asset and inflammatory microenvironment which characterize the disease as amenable target for novel therapeutic approaches.

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