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Which patients might benefit from therapies targeting monopolar spindle 1 kinase (MPS1/TTK) in gliomas?
Welche Patienten könnten von einer gegen monopolar spindle 1 kinase (MPS1/TTK) gerichteten Therapie profitieren?
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Published: | June 26, 2020 |
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Objective: Recently, we demonstrated that the effects of vincristine chemotherapy or Tumour Treating Fields in experimental glioblastoma multiforme (GBM) were augmented and accelerated by inhibition of the protein kinase MPS1, a mitotic spindle checkpoint regulator. It is overexpressed in astrocytic tumours and therefore represents a potential therapeutic target. The purpose of this study was to provide information on MPS1 expression in clinical subgroups of GBM and other gliomas and to evaluate its impact on the patients’ clinical course.
Methods: We analysed MPS1 mRNA expression by qPCR in a collection of GBM (n=57), gliomas WHO grade II/III with (n=25) or without (n=11) IDH mutation, adult pilocytic astrocytomas (n=4) and healthy brain specimens (n=7). Subsequently, we examined associations of MPS1 mRNA expression with the patients’ clinical course.
Results: We confirm MPS1 overexpression in glial tumours (ANOVA, all p<0.01), which was correlated with tumour aggressiveness. Furthermore, we now can explain previously published contrasting results on survival: High MPS1 expression was associated with lower long term survival when all astrocytic tumours were combined in one group (Cox regression: t < 24 months, p=0.009, Hazard ratio=8.0, 95% CI: 1.7-38.4). However, if evaluated separately, it was associated with poorer survival in low-grade gliomas (LogRank: p=0.02, Cox regression: p=0.06, Hazard-Ratio: 8.0, 95% CI: 0.9-66.7), but not with the survival of GBM patients (LogRank: p>0.05). Although GBM patients with high MPS1 developed clinical symptoms at an earlier stage and therefore started treatment with a lower tumour volume (median tumour volume: 45ccm vs. 25ccm, p=0.043, unpaired two-tailed t-test), they did not benefit in terms of overall survival, most likely due to a more aggressive tumour growth. Interestingly, patients with high MPS1 expression more frequently were initially submitted to the hospital with epileptic seizures or focal neurological deficits.
Conclusion: MPS1 mRNA was overexpressed in gliomas, associated with patients’ survival and increased tumor aggressiveness. Therefore, we hypothesize that patients with the worst outcome might benefit best from a treatment directed against MPS1.