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: 10549807
• 负责人: Abrar Choudhury
• 金额: $ 3.23万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10549807
• 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; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Communities; DNA Methylation; DNA methylation profiling; Data; Exposure to; FOXM1 gene; Fellowship; Foundations; Genes; Genetic; Genetic Transcription; Genomics; Goals; Grant; Growth; Histopathologic Grade; Human; In Vitro; Intracranial Neoplasms; Knowledge; Learning; Malignant Neoplasms; 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; Physicians; Physiology; Preparation; Progression-Free Survivals; Proliferating; Radiation; Recurrence; Recurrent tumor; Regulation; Research; Research Personnel; Research Project Grants; Resected; Role; Running; Sampling; Science; Scientist; Specialized Program of Research Excellence; Subgroup; TOP2A gene; Testing; Training; Tumor Biology; Tumor Cell Invasion; Tumor Suppressor Proteins; United States; Writing; cancer type; candidate identification; career; clinical database; demographics; follow-up; improved; meningioma; molecular targeted therapies; neoplastic cell; neuro-oncology; new technology; new therapeutic target; novel; pharmacologic; skills; technology platform; 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.

项目摘要/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 脑膜瘤包括手术和辐射，但大多数高级脑膜瘤复发，并且没有 有效的脑膜瘤患者的全身性或分子疗法。基于DNA甲基化的分类 更好地预测脑膜瘤的结局，而不是组织学等级，这表明了解分子 驱动脑膜瘤生长的机制对于改善患者预后至关重要。肿瘤抑制剂NF2是 脑膜瘤中最常见的基因最常见的基因，但NF2在正常生理学和 肿瘤发生知之甚少。因此，关于发病机理的分子驱动因素知之甚少 在脑膜瘤。该研究项目的总体目标是了解驱动分子途径 脑膜瘤以阐明脑膜瘤患者的新分子疗法。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 人口统计学，基因组特征和临床结果。脑膜瘤最激进的亚组 由FOXM1的富集来定义，FOXM1是一种致癌转录因子，我们的实验室已证明与之相关 高度脑膜瘤和脑膜瘤的生长。 NF2与翻译后有关 FOXM1在其他类型的癌症中的降解。因此，我假设脑膜瘤中NF2的损失稳定 FOXM1表达和活性以驱动侵袭性肿瘤的生长。定义FOXM1驾驶方式 AIM 1脑膜瘤生长提议鉴定并在功能上验证脑膜瘤中的FOXM1靶基因。 为了了解FOXM1如何激活以驱动脑膜瘤，AIM 2将决定FOXM1介导的 脑膜瘤的生长取决于NF2损失。这项研究将在罗利实验室进行 UCSF脑肿瘤中心是NCI认可的专业研究卓越计划（Spore）， 我的导师的指导，脑膜瘤临床和研究专业知识的医师科学家Raleigh博士 生物学和脑肿瘤生物学著名专家Costello博士，成功的悠久记录 指导。该项目将改善我现有的分子和细胞生物学技术知识，创建 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。 作为奖学金培训计划的一部分，我还将学习并融入临床神经肿瘤学 UCSF的社区为我的职业目标做准备，即成为神经综合医生的医生 - 科学家。 此外，我将发展专业技能，例如科学沟通和赠款写作，这是 成为成为独立研究人员实验室的医师科学家至关重要的。