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

Jiaojiao Deng, Lingyang Hua, Tao Han, Mi Tian, Daijun Wang, Hailiang Tang, Shuchen Sun, Hong Chen, Haixia Cheng, Tao Zhang, Qing Xie, Lixin Wan, Hongda Zhu, Ye Gong
Neuro-oncology advances 2020, 2 (1): vdz055

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.

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