Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Deng J

PROVIDER: S-EPMC7212891 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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Publications

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

Deng Jiaojiao J Hua Lingyang L Han Tao T Tian Mi M Wang Daijun D Tang Hailiang H Sun Shuchen S Chen Hong H Cheng Haixia H Zhang Tao T Xie Qing Q Wan Lixin L Zhu Hongda H Gong Ye Y

Neuro-oncology advances 20200101 1

<h4>Background</h4>Meningiomas with Neurofibromin 2 gene mutations (<i>NF2</i>-mutant meningiomas) account for ~40% of the sporadic meningiomas. However, there is still no effective drug treatment for the disease.<h4>Methods</h4>Expression profile of Merlin protein was explored through immunohistochemistry in a meningioma patient cohort (<i>n</i> = 346). A 20-agent library covering a wide range of meningioma relevant targets was tested using meningioma cell lines IOMM-Lee (<i>NF2</i> wildtype) a ...[more]

PMID: 32642722

Similar Datasets

Project description:BACKGROUND: Meningiomas are the most common intracranial neoplasias, representing a clinically and histopathologically heterogeneous group of tumors. The neurofibromatosis type 2 (NF2) tumor suppressor is the only gene known to be frequently involved in early development of meningiomas. The objective of this study was to identify genetic and/or epigenetic factors contributing to the development of these tumors. A large set of sporadic meningiomas were analyzed for presence of 22q macro-mutations using array-CGH in order to identify tumors carrying gene dosage aberrations not encompassing NF2. The NF2 locus was also comprehensively studied for point mutations within coding and conserved non-coding sequences. Furthermore, CpG methylation within the NF2 promoter region was thoroughly analyzed. RESULTS: Monosomy 22 was the predominant finding, detected in 47% of meningiomas. Thirteen percent of the tumors contained interstitial/terminal deletions and gains, present singly or in combinations. We defined at least two minimal overlapping regions outside the NF2 locus that are small enough (approximately 550 kb and approximately 250 kb) to allow analysis of a limited number of candidate genes. Bialleinactivationo the NF2 gne was detected in 36% of meningiomas. Among the monosomy 22 cases, no additional NF2 mutations could be identified in 35% (17 out of 49) of tumors. Furthermore, the majority of tumors (9 out of 12) with interstitial/terminal deletions did not have any detectable NF2 mutations. Methylation within the NF2 promoter region was only identified at a single CpG site in one tumor sample. CONCLUSION: We confirmed previous findings of pronounced differences in mutation frequency between different histopathological subtypes. There is a higher frequency of biallelic NF2 inactivation in fibroblastic (52%) compared to meningothelial (18%) tumors. The presence of macro-mutations on 22q also shows marked differences between fibroblastic (86%) and meningothelial (39%) subtypes. Thus, inactivation of NF2, often combined with the presence of macro-mutation on 22q, is likely not as important for the development of the meningothelial subtype, as opposed to the fibroblastic form. Analysis of 40 CpG sites distributed within 750 bp of the promoter region suggests that NF2 promoter methylation does not play a major role in meningioma development.