The CREB-binding protein inhibitor ICG-001: a promising therapeutic strategy in sporadic meningioma with NF2 mutations.

Background: Meningiomas with Neurofibromin 2 gene mutations ( NF2 -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 ( n = 346). A 20-agent library covering a wide range of meningioma relevant targets was tested using meningioma cell lines IOMM-Lee ( NF2 wildtype) and CH157-MN ( NF2 deficient). Therapeutic effects and biological mechanisms of the identified compound, ICG-001, in NF2 -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 NF2 -mutant xenografts in mice, as well. We also provide further evidence that ICG-001 inhibits proliferation of NF2 -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 NF2 -mutant meningioma.