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.

项目概要中枢神经系统的脑膜内层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部分。脑膜瘤是绝大多数在老年人、女性和非裔美国患者中被诊断出，所有这些患者在临床试验中代表性不足。因此，脑膜瘤尚无有效的药物治疗方法患者。由于对脑膜瘤生物学的了解有限以及对脑膜瘤的了解有限，新疗法进一步受到阻碍。缺乏临床前脑膜瘤研究的易处理模型。为了解决这些问题，我们执行了对 565 例人类脑膜瘤患者进行多平台分子分析，并提供全面的随访数据发现脑膜瘤由 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脑类器官和患者衍生的异种移植模型脑膜瘤。我们在本申请中提供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，CDK6 水平的细胞周期失活。我们的中心假设是 CDK6 是脑膜瘤生长所必需的，临床 CDK4/6 抑制剂将在临床前脑膜瘤模型中表现出活性。为了检验这个假设，我们将定义功效和生物标志物脑膜瘤对 CDK4/6 抑制剂的反应，定义 CDK6 的分子机制脑膜瘤中的错误激活，并确定减轻脑膜瘤中 CDK4/6 阻断耐药性的途径。我们的提案将整合人类样本、脑膜瘤肿瘤发生的类器官模型以及正在研究的具有 CRISPR 干扰和药理学作用的患者来源的异种移植物。这种方法的前提是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。我们对脑膜瘤如何发展知之甚少，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，以开发有针对性的治疗方法将改善脑膜瘤患者的治疗和结果的策略。因此，这项工作不仅解释脑膜瘤如何生长，还将阐明药物机制并建立临床前研究基金会支持脑膜瘤患者的新临床试验。