Upregulated spindle pathway genes identified in aggressive mesothelioma
medwireNews: Malignant pleural mesothelioma (MPM) can be stratified according to three distinct molecular subtypes, a finding that could be of potential therapeutic importance, report US researchers.
They discovered that the miotic spindle assembly checkpoint (MSAC) pathway is significantly altered in MPM tissue, with upregulation of genes including MAD2L1, and that the non-taxane small molecule inhibitor epothilone B decreases the viability of MPM cancer cells in culture.
“[T]hese newly discovered molecular subgroups and networks based on gene expression profiles will reveal effective treatment strategies for MPM patients in a personalized medicine era”, remark Ignacio Wistuba (The University of Texas MD Anderson Cancer Center, Houston) and fellow researchers.
The team carried out microarray analysis on total RNA extracted from 53 surgically resected MPM tumour samples, as well as 38 non-tumourous paired tissue samples. Approximately 2310 probe sets, representing 1746 genes, were obtained. Pathway analysis of these genes revealed the MSAC pathway to be the most significantly deregulated in the MPM samples, as well as to contain 18 upregulated components including MAD2L1, BUB1 and AURKA.
Interestingly, note Wistuba et al in the Annals of Oncology, robust cluster analysis of the initial probe sets revealed three molecular subgroups of tumours with differential transcript expression. However, these subgroups did not correlate with histological subtypes or clinicopathological outcomes such as patient survival.
To validate their microarray analysis, the researchers focused on MAD2L1, which was expressed at high levels compared with healthy tissues, and which is a “well-documented indicator of the deregulated status of the MSAC pathway.”
The mean expression of MAD2L1 protein observed in tumour samples was significantly increased compared with that seen in healthy tissue and, notably, there was significantly higher cytoplasmic expression among MPM tumours with lymph node metastases, compared with samples from nonmetastatic disease, with mean expression scores of 57.1 versus 33.2.
In univariate analysis, higher nuclear levels of MAD2L1 protein also correlated with lower overall survival rates, note Wistuba and colleagues.
They next tested the efficacy of commercially available drugs that target kinases, in particular epothilone B, a non-taxane microtubule inhibitor. Of all drugs tested, this was the most effective at inhibiting proliferation of 14 MPM tissue lines, with a median IC50 (measuring the effectiveness of a substances' ability to inhibit biological function) of 1.5 n/M.
“This raises the interesting possibility that non-taxane microtubule-targeting therapy might prove to be of benefit in treatment of mesothelioma patients”, concludes the research team.
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By Sarah Pritchard, medwireNews Reporter