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.
Meningioma is the most common primary intracranial tumor in the United States, yet the molecular drivers of meningioma are unknown and there are no effective molecular therapies for meningioma patients. Using a combination of human samples, biochemistry, genomics, and cerebral organoid models, this proposal aims to define and investigate the molecular pathways driving aggressive meningiomas. In addition to advancing understanding of meningioma biology, this proposal will shed light on new therapeutic targets to inhibit meningioma growth.
