The CREB-binding protein inhibitor ICG-001: a promising therapeutic strategy in sporadic meningioma with mutations.

BACKGROUND

Meningiomas with Neurofibromin 2 gene mutations (-mutant meningiomas) account for ~40% of the sporadic meningiomas. However, there is still no effective drug treatment for the disease.

METHODS

Expression profile of Merlin protein was explored through immunohistochemistry in a meningioma patient cohort ( = 346). A 20-agent library covering a wide range of meningioma relevant targets was tested using meningioma cell lines IOMM-Lee ( wildtype) and CH157-MN ( deficient). Therapeutic effects and biological mechanisms of the identified compound, ICG-001, in -mutant meningiomas were further characterized in vitro and in patient-derived xenograft (PDX) models.

RESULTS

Low Merlin expression was associated with meningioma proliferation and poor clinical outcomes in a large patient series. ICG-001, a cAMP-responsive element binding (CREB)-binding protein (CBP) inhibitor, selectively suppressed tumor growth of cells with low Merlin expression. Besides, ICG-001 mediated CH157-MN and IOMM-Lee growth inhibition primarily through robust induction of the G1 cell-cycle arrest. Treatment with ICG-001 alone significantly reduced the growth of -mutant xenografts in mice, as well. We also provide further evidence that ICG-001 inhibits proliferation of -mutant meningioma cells at least partly through attenuating the FOXM1-mediated Wnt/β-catenin signaling.

CONCLUSIONS

This study highlights the importance of ligand-mediated Wnt/β-catenin signaling as well as its drugable potency in -mutant meningioma.