Understanding druggable drivers of meningioma tumorigenesis

了解脑膜瘤肿瘤发生的药物驱动因素

基本信息

批准号：
10275399
负责人：
David R Raleigh
金额：
$ 51.74万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10275399
关键词：
Address African American Automobile Driving Biochemical Biochemistry Biology Brain Neoplasms CDK4 gene CRISPR interference CRISPR screen California Cell Cycle Cell Cycle Inhibition Cell Line Cell Proliferation Cells Cerebrum ChIP-seq Clinical Clinical Research Clinical Trials Coculture Techniques Collaborations Copy Number Polymorphism Cyclin-Dependent Kinase Inhibitor 2A DNA Probes DNA methylation profiling Data Developmental Therapeutics Program Diagnosis Drug Kinetics Elderly Enhancers Epigenetic Process Foundations Future Genetic Goals Growth Hand Histologic Histology Homeostasis Hong Kong Human In Vitro Intracranial Neoplasms Investigation Light Malignant Intracranial Neoplasm Malignant Neoplasms Meningeal Meningeal Neoplasms Modeling Molecular Molecular Profiling Morbidity - disease rate Mus Neuraxis Neurologic Normal tissue morphology Oncogenic Organoids Outcome Pathway interactions Patients Pharmacodynamics Pharmacological Treatment Pharmacology Pre-Clinical Model Process Reagent Recurrence Research Resistance Sampling San Francisco Signal Transduction Study models Subgroup TP53 gene Testing Therapeutic Tissues Treatment outcome Tumor Tissue USF1 gene Universities Woman Work Xenograft procedure base cohort experience follow-up genome-wide improved inhibitor/antagonist innovation insight meningioma mortality mouse model neuron development new therapeutic target novel novel therapeutics patient derived xenograft model pharmacokinetics and pharmacodynamics pre-clinical preclinical study predict clinical outcome prevent promoter resistance mechanism response biomarker success targeted treatment transcription factor transcriptome sequencing tumor tumor growth tumorigenesis

项目摘要

Project summary The meningeal lining of the central nervous system is critical for neuronal development and homeostasis. However, meningeal tumors account for the majority of primary intracranial cancers. Meningiomas are overwhelmingly diagnosed in older adults, women, and African American patients, all of which are underrepresented in clinical trials. Thus, there are no effective pharmacologic treatments for meningioma patients. New therapies have been further encumbered by limited understanding of meningioma biology and a lack of tractable models for preclinical meningioma investigation. To address these problems, we performed multiplatform molecular profiling on 565 human meningiomas from patients with comprehensive follow-up data to discover that meningioma is comprised of 3 epigenetic subgroups with distinct clinical outcomes. Moreover, we recently developed novel cerebral organoid and patient derived xenograft models for each subgroup of meningiomas. Our preliminary data presented in this application reveal convergent genetic mechanisms misactivating the cell cycle at the level of CDK6 in the subgroup of meningiomas with the worst clinical outcomes. Our central hypothesis is that CDK6 is required for meningioma growth, and that clinical CDK4/6 inhibitors will show activity in preclinical meningioma models. To test this hypothesis, we will define the efficacy and biomarkers of response to CDK4/6 inhibitors in meningioma, define the molecular mechanisms underlying CDK6 misactivation in meningiomas, and identify pathways mitigating resistance to CDK4/6 blockade in meningioma. Our proposal will integrate human samples, organoid models of meningioma tumorigenesis, and understudied patient derived xenografts with CRISPR interference and pharmacology. This approach is based on the premise that improving treatments for meningioma patients depends on our ability to identify and target key molecular mechanisms driving meningioma cell proliferation. We know surprisingly little about how meningiomas develop, and almost nothing about how to block the molecular mechanisms underlying meningioma growth. Though the short-term objective of this proposal is to broadly improve our understanding of meningioma cell proliferation, a long-term goal of this research is to understand this process well enough to develop targeted therapeutic strategies that will improve treatments and outcomes for meningioma patients. Thus, this work will not only explain how meningiomas grow, but will also elucidate druggable mechanisms and establish preclinical foundation to support new clinical trials for meningioma patients.

项目摘要中枢神经系统的脑膜内膜对于神经元发展和体内平衡至关重要。但是，脑膜肿瘤占大多数原发性颅内癌症。脑膜瘤是在老年人，妇女和非裔美国人患者中被压倒性地被诊断出来在临床试验中的代表性不足。因此，没有有效的脑膜瘤药理治疗患者。对脑膜瘤生物学和A 缺乏用于临床前脑膜瘤研究的可疗法模型。为了解决这些问题，我们执行了来自具有全面随访数据的患者的565人脑膜瘤的乘数分子分析发现脑膜瘤由3个具有不同临床结果的表观遗传亚组组成。而且，我们最近为每个亚组开发了新型的大脑器官和患者衍生的异种移植模型脑膜瘤。我们在本应用程序中提供的初步数据揭示了收敛的遗传机制在脑膜瘤亚组中误导了CDK6水平的细胞周期，其临床结果最差。我们的中心假设是脑膜瘤生长需要CDK6，临床CDK4/6抑制剂将在临床前脑膜瘤模型中显示活性。为了检验这一假设，我们将定义功效和生物标志物对脑膜瘤中CDK4/6抑制剂的反应，定义了CDK6的分子机制脑膜瘤中的误导，并确定途径减轻脑膜瘤中CDK4/6封锁的抗性。我们的建议将整合人类样品，脑膜瘤肿瘤发生的器官模型，并研究了患者衍生出具有CRISPR干扰和药理学的异种移植物。这种方法基于前提改善脑膜瘤患者的治疗方法取决于我们识别和靶向关键分子的能力驱动脑膜瘤细胞增殖的机制。我们对脑膜瘤的发展方式一无所知，几乎没有关于如何阻止脑膜瘤生长的分子机制。虽然该提案的短期目标是广泛地提高我们对脑膜瘤细胞增殖的理解，一个这项研究的长期目标是足够理解这一过程，以开发有针对性的治疗性将改善脑膜瘤患者治疗和结果的策略。因此，这项工作不仅会解释脑膜瘤如何生长，但也将阐明可药物的机制并建立临床前支持脑膜瘤患者的新临床试验的基金会。