Investigating the Regulation and Role of FOXM1 in Aggressive Meningioma

项目总结/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 脑膜瘤包括手术和放射治疗，但大多数高级别脑膜瘤复发， 有效的系统或分子治疗脑膜瘤患者。基于DNA甲基化的分类 更好地预测脑膜瘤的结果比组织学分级，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。肿瘤抑制因子NF 2是 脑膜瘤中最常见的突变基因，但NF 2在正常生理和 肿瘤发生仍然知之甚少。因此，对致病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分子途径驱动 脑膜瘤，以阐明脑膜瘤患者的新型分子疗法。我们的初步数据 表明脑膜瘤由4个分子亚群组成，与不同的患者相关， 人口统计学、基因组特征和临床结果。脑膜瘤最具侵袭性的亚组 通过FOXM 1的富集来定义，FOXM 1是一种致癌转录因子， 高级别脑膜瘤和脑膜瘤生长。NF 2参与了翻译后 FOXM 1在其他类型癌症中的降解。因此，我假设脑膜瘤中NF 2的丢失稳定了 FOXM 1表达和活性驱动侵袭性肿瘤的生长。要定义FOXM 1如何驱动 为了研究FOXM 1在脑膜瘤生长中的作用，目的1提出了在脑膜瘤中鉴定和功能验证FOXM 1靶基因。 为了了解FOXM 1是如何被激活以驱动脑膜瘤的，Aim 2将确定FOXM 1介导的脑膜瘤是否是由FOXM 1介导的。 脑膜瘤的生长取决于NF 2的丢失。这项研究将在罗利实验室进行， UCSF脑肿瘤中心，NCI认可的卓越研究专业计划（SPORE），根据 在我的导师罗利博士的指导下，他是一位在脑膜瘤方面具有临床和研究专长的医生兼科学家 科斯特洛博士，一位著名的脑肿瘤生物学专家，有着长期的成功治疗记录。 导师制这个项目将提高我现有的分子和细胞生物学技术知识， 接触新技术和模型系统，并发展生物化学和生物信息学的新技能。 作为奖学金培训计划的一部分，我也将学习并融入临床神经肿瘤学 在UCSF的社区，为我成为一名神经肿瘤学家的职业目标做准备。 此外，我将发展专业技能，如科学交流和拨款写作，这是 成为一名独立研究员，管理实验室的物理学家和科学家。

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.