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NF2-associated meningiomas: From omics discovery to targeted therapy

NF2 相关脑膜瘤：从组学发现到靶向治疗

基本信息

批准号：
10408180
负责人：
VIJAYA RAMESH
金额：
$ 63.28万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10408180
关键词：
14q APLN gene Acoustic Neuroma Adult Alleles Anaplastic Meningioma Animal Model Arachnoid mater Back Benign Meningiomas Biological CRISPR/Cas technology Cell Line Cell model Cells Clinical Clinical Trials Collaborations Dasatinib Data Drug Combinations Drug Screening Drug Targeting ERBB3 gene Enzymes Eph Family Receptors Exhibits FRAP1 gene Future Genetic Heterogeneity Genetic Transcription Genomic Instability Growth Growth Factor Heregulin Human IGF1R gene Implant In Vitro Intracranial Neoplasms Ligands Luciferases Maximum Tolerated Dose Measures Modeling Monitor Morbidity - disease rate Mus Mutation NRG1 gene Names National Center for Advancing Translational Sciences Neuregulins Neurofibromatosis 2 Null Lymphocytes Ohio Operative Surgical Procedures Outcome Study Pathway interactions Pediatric Hospitals Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phosphotransferases Play Proteasome Inhibitor Protein Tyrosine Kinase Proto-Oncogene Protein c-kit Public Health Publishing Radiation Randomized Receptor Protein-Tyrosine Kinases Regulation Research Resected Role SDZ RAD Screening Result Signal Pathway Signal Transduction Skull Base Neoplasms System Systemic Therapy Testing Time Translating Tumor Suppressor Genes Ubiquitin Ubiquitin-Activating Enzymes United States National Institutes of Health Up-Regulation Work antitumor effect base bioluminescence imaging chromosome 22q loss clinical care clinical development comparative genomic hybridization cytotoxic drug efficacy effective therapy follow-up genome editing heparin-binding EGF-like growth factor in vivo in vivo Model in vivo evaluation inhibitor mTOR Inhibitor member meningioma mortality mouse model multicatalytic endopeptidase complex neoplastic cell novel novel therapeutic intervention pre-clinical response single-cell RNA sequencing small molecule inhibitor src-Family Kinases targeted treatment therapeutic target transcriptome transcriptome sequencing tumor tumor growth tumor heterogeneity

项目摘要

Neurofibromatosis 2 (NF2) is characterized by vestibular schwannomas, and meningiomas that show loss of the NF2 tumor suppressor gene. Meningiomas arise from meningothelial arachnoid cap cells and are the most common primary intracranial tumors in adults. NF2 inactivation is frequently associated with sporadic meningiomas, particularly in primary atypical (WHO grade II) tumors. Meningiomas that progress despite surgery and radiation are responsible for significant morbidity and mortality. Therefore, effective systemic therapies are greatly needed. For meningioma modeling and preclinical drug screening, we employ human primary meningioma (MN) cell lines derived from surgically resected tumors and CRISPR-Cas9 genome-edited isogenic, human arachnoidal cell lines (ACs) that either express or lack NF2. Employing these models, we established that NF2-deficient meningiomas reveal aberrant activation of mTORC1/mTORC2 signaling, which led to clinical trials for NF2 and meningiomas. Recently, we undertook large-scale kinome, transcriptome and drug screening studies in our AC and MN cell models to identify other potential targets. Kinome and transcriptome data revealed increased activation and expression of several EPH receptor family tyrosine kinases (EPH-RTKs), Src family kinase members (SFKs) and c-KIT, which are all targets of dasatinib, which is recently published. Our ‘omics approach also identified other interesting candidates, including ligands NRG1, HBEGF and apelin, and AMPK-related kinases, particularly NUAK2, to be consistently upregulated in the kinome and transcriptome of NF2-null AC/MN cells. Our recent results suggest that NRG1 expression and ERBB3 signaling is regulated by mTORC1 signaling. We plan to examine whether NRG1 alone or factors such as HBEGF and APLN are also regulated by mTOR or play a role in downstream signaling in NF2-null MN cells. We propose to understand the mechanism and biological significance of elevated expression and activation of NUAK2 in meningioma. Further, our large-scale drug screening efforts, in collaboration with NIH-NCATS, revealed a set of proteasome pathway related drugs exhibiting cytotoxic effects in NF2-null cells. Here we propose to examine three different drugs targeting the proteasome (provided by Millennium-Takeda Pharmaceuticals), alone and combined with TAK-228 (mTOR inhibitor) in 5 grade I, 5 grade II and 5 grade III MN lines with NF2 loss. More importantly, we propose to undertake single cell RNAseq along with array CGH in NF2-deficient meningiomas and their corresponding primary cell lines to define tumor heterogeneity and correlate with drug response. Anti-tumor efficacy of proteasome drugs will also be evaluated in orthotopic NF2- deficient benign and malignant meningioma models. Our overall approach of (i) leveraging the ‘omics and drug screening results, (ii) characterizing tumor heterogeneity and correlating with drug response, and (iii) testing potential drugs in orthotopic NF2-deficient in vivo models is timely, novel and will provide a framework to pursue new avenues in NF2 and meningioma research for clinical care.

神经纤维瘤病2（NF 2）的特征是前庭神经鞘瘤和脑膜瘤， NF 2肿瘤抑制基因。脑膜瘤起源于脑膜瘤蛛网膜帽细胞，成人常见的原发性颅内肿瘤。NF 2失活经常与散发性脑膜瘤，特别是原发性非典型（WHO II级）肿瘤。脑膜瘤的进展，外科手术和放射治疗是导致显著发病率和死亡率的原因。因此，有效的系统非常需要治疗。对于脑膜瘤建模和临床前药物筛选，我们采用人类来源于手术切除的肿瘤和CRISPR-Cas9基因组编辑的原发性脑膜瘤（MN）细胞系表达或缺乏NF 2的等基因人蛛网膜细胞系（AC）。利用这些模型，我们 NF 2缺陷型脑膜瘤显示mTORC 1/mTORC 2信号异常激活，导致了NF 2和脑膜瘤的临床试验。最近，我们进行了大规模的激酶组，转录组和在我们的AC和MN细胞模型中进行药物筛选研究，以确定其他潜在的靶点。Kinome和转录组数据显示几种EPH受体家族酪氨酸的激活和表达增加激酶（EPH-RTK）、Src家族激酶成员（SFK）和c-KIT，它们都是达沙替尼的靶点，最近出版的。我们的组学方法还确定了其他有趣的候选者，包括配体NRG 1， HBEGF和apelin以及AMPK相关激酶，特别是NUAK 2，在肿瘤细胞中持续上调。 NF 2缺失AC/MN细胞的激酶组和转录组。我们最近的研究结果表明，NRG 1的表达和 ERBB 3信号由mTORC 1信号调节。我们计划研究NRG 1是否单独或因素，因为HBEGF和APLN也受mTOR调节，或在NF 2缺失的MN细胞中的下游信号传导中起作用。我们建议了解的机制和生物学意义的表达和激活的升高，脑膜瘤中的NUAK 2。此外，我们与NIH-NCATS合作进行的大规模药物筛选工作，揭示了一组蛋白酶体途径相关的药物，其在NF 2缺失细胞中表现出细胞毒性作用。这里我们我建议检查三种不同的靶向蛋白酶体的药物（由Millennium Takeda提供药物），单独给药和与TAK-228（mTOR抑制剂）联合给药，5例I级、5例II级和5例III级患者 NF 2损失的MN线。更重要的是，我们建议进行单细胞RNAseq沿着阵列CGH 在NF 2缺陷型脑膜瘤及其相应的原代细胞系中确定肿瘤异质性，与药物反应有关。蛋白酶体药物的抗肿瘤功效也将在原位NF 2-κ B中进行评估。缺陷的良性和恶性脑膜瘤模型。我们的总体方法是（i）利用“组学和药物” 筛选结果，（ii）表征肿瘤异质性并与药物反应相关，和（iii）测试在原位NF 2缺陷的体内模型中的潜在药物是及时的，新颖的，并将提供一个框架，寻求NF 2和脑膜瘤研究的新途径，用于临床护理。