Investigating the Regulation and Role of FOXM1 in Aggressive Meningioma

研究 FOXM1 在侵袭性脑膜瘤中的调节和作用

• 批准号: 10092806
• 负责人: Abrar Choudhury
• 金额: $ 3.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092806
• 关键词: Automobile Driving; Biochemistry; Bioinformatics; Biological; Biological Assay; Biological Models; Biology; Brain Neoplasms; Cell Proliferation; Cells; Cellular biology; Central Nervous System Neoplasms; Cerebrum; ChIP-seq; Characteristics; Classification; Clinical; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Community Clinical Oncology Program; DNA Methylation; DNA methylation profiling; Data; Exposure to; FOXM1 gene; Fellowship; Foundations; Genes; Genetic; Genetic Transcription; Genomics; Goals; Grant; Growth; Histologic; Histopathologic Grade; Human; In Vitro; Intracranial Neoplasms; Knowledge; Learning; Light; Mediating; Mentors; Mentorship; Mitotic; Modeling; Molecular; Molecular Biology; Mutate; Mutation; Neurofibromin 2; Oncogenic; Oncologist; Operative Surgical Procedures; Organoids; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Physicians; Physiology; Preparation; Progression-Free Survivals; Radiation; Regulation; Research; Research Personnel; Research Project Grants; Resected; Role; Running; Sampling; Science; Scientist; Specialized Program of Research Excellence; Subgroup; Syndrome; TOP2A gene; Testing; Training; Tumor Biology; Tumor Cell Invasion; Tumor Suppressor Proteins; United States; Writing; base; cancer type; career; clinical database; demographics; follow-up; improved; meningioma; molecular targeted therapies; neoplastic cell; neuro-oncology; new technology; new therapeutic target; novel; skills; transcription factor; transcriptome sequencing; tumor; tumorigenesis

PROJECT SUMMARY/ABSTRACT Meningioma is the most common primary central nervous system tumor in the United States. Treatments for meningiomas include surgery and radiation, but the majority of high-grade meningiomas recur, and there are no effective systemic or molecular therapies for meningioma patients. A classification based on DNA methylation better predicts meningioma outcomes than histologic grade, suggesting that understanding the molecular mechanisms driving meningioma growth is critical for improving patient outcomes. The tumor suppressor NF2 is the most commonly mutated gene in meningioma, but how NF2 functions in normal physiology and tumorigenesis remains poorly understood. Thus, very little is known about the molecular drivers of pathogenesis in meningioma. The overall goal of this research project is to understand the molecular pathways driving meningioma in order to shed light on novel molecular therapies for meningioma patients. Our preliminary data demonstrate that meningioma is comprised of 4 molecular subgroups that are associated with distinct patient demographics, genomic characteristics, and clinical outcomes. The most aggressive subgroup of meningiomas is defined by enrichment of FOXM1, an oncogenic transcription factor that our lab has shown to be associated with high-grade meningiomas and meningioma growth. NF2 has been implicated in post-translational degradation of FOXM1 in other types of cancer. Thus, I hypothesize that loss of NF2 in meningioma stabilizes FOXM1 expression and activity to drive the growth of aggressive tumors. To define how FOXM1 drives meningioma growth, Aim 1 proposes to identify and functionally validate FOXM1 target genes in meningioma. To understand how FOXM1 is activated to drive meningioma, Aim 2 will determine whether FOXM1-mediated meningioma growth is contingent on NF2 loss. This research will be conducted in the Raleigh lab, within the UCSF Brain Tumor Center, an NCI-recognized Specialized Program of Research Excellence (SPORE), under the guidance of my mentors, Dr. Raleigh, a physician-scientist with clinical and research expertise in meningioma biology, and Dr. Costello, a renowned expert in brain tumor biology with a long track record of successful mentorship. This project will improve upon my existing molecular and cell biology technical knowledge, create exposure to new technologies and model systems, and develop new skillsets in biochemistry and bioinformatics. As part of the fellowship training plan, I will also learn from and integrate into the clinical neuro-oncology community at UCSF, in preparation for my career goal of becoming a neuro-oncologist physician-scientist. Furthermore, I will develop professional skills, such as science communication and grant writing, which are essential for becoming a physician-scientist running a lab as an independent researcher.

项目概要/摘要 脑膜瘤是美国最常见的原发性中枢神经系统肿瘤。治疗方法 脑膜瘤包括手术和放射治疗，但大多数高级别脑膜瘤会复发，并且没有 对脑膜瘤患者有效的全身或分子疗法。基于DNA甲基化的分类 比组织学分级更好地预测脑膜瘤结果，这表明了解分子水平 驱动脑膜瘤生长的机制对于改善患者的预后至关重要。肿瘤抑制因子 NF2 是 NF2 是脑膜瘤中最常见的突变基因，但 NF2 在正常生理学中如何发挥作用？ 肿瘤发生仍知之甚少。因此，对于发病机制的分子驱动因素知之甚少 在脑膜瘤中。该研究项目的总体目标是了解驱动的分子途径 脑膜瘤，以揭示脑膜瘤患者的新型分子疗法。我们的初步数据 证明脑膜瘤由与不同患者相关的 4 个分子亚组组成 人口统计、基因组特征和临床结果。最具侵袭性的脑膜瘤亚组 是通过 FOXM1 的富集来定义的，FOXM1 是一种致癌转录因子，我们的实验室已证明与此相关 伴有高级别脑膜瘤和脑膜瘤生长。 NF2 与翻译后 FOXM1 在其他类型癌症中的降解。因此，我假设脑膜瘤中 NF2 的缺失会稳定下来 FOXM1 表达和活性可驱动侵袭性肿瘤的生长。定义 FOXM1 如何驱动 脑膜瘤生长，目标 1 建议识别脑膜瘤中的 FOXM1 靶基因并进行功能验证。 为了了解 FOXM1 如何被激活以驱动脑膜瘤，目标 2 将确定 FOXM1 是否介导 脑膜瘤的生长取决于 NF2 的丧失。这项研究将在罗利实验室进行 UCSF 脑肿瘤中心是 NCI 认可的专业卓越研究计划 (SPORE)，隶属于 我的导师 Raleigh 博士的指导，他是一位拥有脑膜瘤临床和研究专业知识的医师科学家 Costello 博士是脑肿瘤生物学领域的著名专家，拥有长期的成功记录 指导。该项目将改进我现有的分子和细胞生物学技术知识，创造 接触新技术和模型系统，并开发生物化学和生物信息学方面的新技能。 作为进修培训计划的一部分，我还将学习并融入临床神经肿瘤学 加州大学旧金山分校社区，为我成为一名神经肿瘤学家医师科学家的职业目标做准备。 此外，我将发展专业技能，例如科学传播和资助写作，这些技能 对于成为一名以独立研究员身份经营实验室的医师科学家至关重要。