Understanding druggable drivers of meningioma tumorigenesis

了解脑膜瘤肿瘤发生的药物驱动因素

• 批准号: 10456201
• 负责人: David R Raleigh
• 金额: $ 56.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/10456201
• 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; 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

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衬里对于神经元发育和体内平衡至关重要。 然而，脑膜肿瘤占原发性颅内癌的大多数。脑膜瘤是 绝大多数老年人，妇女和非裔美国人患者被诊断出来，所有这些都是 在临床试验中代表性不足。因此，脑膜瘤没有有效的药物治疗 患者由于对脑膜瘤生物学的了解有限， 缺乏用于临床前脑膜瘤研究的易处理模型。为了解决这些问题，我们 对565例具有全面随访数据的人脑膜瘤患者进行多平台分子分析 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。此外，委员会认为， 我们最近开发了新的脑类器官和患者来源的异种移植模型，用于每个亚组， 脑膜瘤我们在本申请中提出的初步数据揭示了趋同遗传机制 在临床结果最差的脑膜瘤亚组中，CDK 6水平的细胞周期错误激活。 我们的中心假设是CDK 6是脑膜瘤生长所必需的，临床上使用CDK 4/6抑制剂将 在临床前脑膜瘤模型中显示活性。为了验证这一假设，我们将定义疗效和生物标志物 脑膜瘤对CDK 4/6抑制剂的反应，定义CDK 6的分子机制 在脑膜瘤中的错误激活，并确定减轻脑膜瘤对CDK 4/6阻断的抵抗的途径。 我们的建议将整合人类样本，脑膜瘤肿瘤发生的类器官模型， 具有CRISPR干扰和药理学的患者来源的异种移植物。这种方法是基于这样的前提： 改善脑膜瘤患者的治疗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所知甚少， 几乎没有关于如何阻止脑膜瘤生长的分子机制。虽然 这项建议的短期目标是广泛地提高我们对脑膜瘤细胞增殖的理解， 这项研究的长期目标是充分了解这一过程，以开发靶向治疗药物。 改善脑膜瘤患者治疗和预后的策略。因此，这项工作不仅 解释脑膜瘤如何生长，但也将阐明药物机制，并建立临床前 基金会支持脑膜瘤患者的新临床试验。