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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘