The CREB-Binding Protein Inhibitor Underlying a Promising Therapeutic Strategy in NF2-associated Meningioma
会议名称：《第十四届中国医师协会神经外科医师年会》
会议日期：2019年
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
关 键 词：Meningioma NF2 Merlin ICG-001 FOXM1 β-Catenin
摘 要：Background: Neurofibromin 2（NF2）-associated meningiomas often cause severe neurologic morbidity and mortality without clearly effective medical treatments. Herein, to uncover novel therapeutic avenues in NF2-associated meningiomas, a focused drug screening in meningioma cells with different Merlin expression pattern was performed in present study. Methods: A total of 346 patients with meningiomas was followed up. A 20-agent library covering a wide range of meningioma relevant targets was screened with 10 high-grade patient-derived meningioma cell lines, malignant meningioma cell lines IOMM-Lee（NF2 wildtype）, CH157-MN（NF2 deficient） and human astrocyte cell line HA1800. Therapeutic effects and biological mechanisms of the lead compound, ICG-001, in NF2-associated meningiomas were characterized in vitro and in patient-derived xenograft（PDX） models. Results: We found low Merlin expression is associated with meningioma proliferation and poor clinical outcomes in a large patient series（n=346）. Interestingly, loss of Merlin expression in high grade meningioma cells rendered sensitivity to ICG-001, a cA MP-responsive element binding（CREB）-binding protein（CBP） inhibitor. Treatment with ICG-001 alone reduced growth of NF2-associated xenografts in mice, as well. Mechanistically, ICG-001 reduces mitotic slippage and self-renewal in NF2-associated meningioma cells by inhibiting CBP function as a coactivator of Wnt/β-catenin-mediated transcription. We also provide further evidence that ICG-001 inhibits proliferation of NF2-associated meningioma cells at least partly through attenuating the FOXM1-mediated Wnt/β-Catenin ***: This study provides a rationale for the clinical evaluation of CBP inhibitors in the treatment of patients with NF2-associated meningiomas. Our findings uncover a novel mechanism of Merlin/FOXM1/β-Catenin pathway to reduce cellular growth through therapeutic administration of ICG-001 in meningiomas.