Investigating the Regulation and Role of FOXM1 in Aggressive Meningioma

项目摘要/摘要 脑膜瘤是美国最常见的原发中枢神经系统肿瘤。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，而且没有 脑膜瘤患者的有效系统或分子治疗。一种基于DNA甲基化的分类 与组织学分级相比，更好地预测脑膜瘤的预后，这表明对分子水平的了解 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NF2是 脑膜瘤中最常见的突变基因，但NF2如何在正常生理和 肿瘤的发生机制仍然知之甚少。因此，人们对致病的分子驱动因素知之甚少。 脑膜瘤。这一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分子疗法。我们的初步数据 证明脑膜瘤由4个分子亚群组成，它们与不同的患者相关 人口学、基因组特征和临床结果。脑膜瘤中最具侵袭性的亚型 是通过富含FOXM1来定义的，FOXM1是一种致癌转录因子，我们的实验室已经证明与之相关 伴有高级别脑膜瘤和脑膜瘤生长。NF2已被牵连到翻译后 FOXM1在其他类型癌症中的降解。因此，我假设脑膜瘤中NF2的丢失是稳定的。 FOXM1的表达和活性推动侵袭性肿瘤的生长。定义FOXM1如何驱动 脑膜瘤生长，目标1建议识别和功能验证脑膜瘤的FOXM1靶基因。 为了了解FOXM1是如何被激活来驱动脑膜瘤的，Aim 2将确定FOXM1介导的 脑膜瘤的生长取决于NF2的缺失。这项研究将在罗利实验室进行， 加州大学旧金山分校脑瘤中心，NCI认可的卓越研究专业计划(孢子)，在 我的导师罗利博士是一位在脑膜瘤方面具有临床和研究专长的内科科学家 和科斯特洛博士，他是一位著名的脑瘤生物学专家，有很长的成功记录 师徒关系。这个项目将改善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，开发生物化学和生物信息学方面的新技能。 作为团契培训计划的一部分，我还将学习并融入临床神经肿瘤学。 在加州大学旧金山分校的社区，为我成为一名神经肿瘤学家、内科医生和科学家的职业目标做准备。 此外，我还将培养专业技能，如科学交流和拨款写作，这些技能包括 成为一名内科科学家，以独立研究员的身份管理实验室，这是必不可少的。

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.