BAF Complex-Mediated Chromatin Dysregulation Driving Meningioma Formation
Abstract
Meningiomas, which are the most common primary brain and spinal tumor, are currently treated with invasive interventions (e.g., neurosurgery, brain/spine radiation) when they cause neurologic symptoms such as seizures, weakness, strokes, or blindness. Unfortunately, there are currently no medical or chemotherapeutic options available for treatment, even for the meningiomas that have a less aggressive clinical course. Victoria Clark, MD, PhD, is a fourth-year neurosurgery resident and post-doctoral research fellow with dual appointments at the Massachusetts General Hospital and the Whitehead Institute for Biomedical Research/Massachusetts Institute of Technology. As a neurosurgeon-scientist in training, her career goal is to investigate the drivers of meningioma formation in order to create less-invasive treatment options for patients. The Horizon Award will provide support for her study of how a gene called SMARCB1, which is important for normal brain development and is mutated in a subset of meningiomas, leads to brain tumor formation and whether a medication that targets a complex of proteins that works in opposition to SMARCB1 has potential therapeutic value for these patients. To facilitate her study of these tumor formation processes, she will be mentored by Dr. Richard A. Young, an expert in the field of how normal cellular and developmental processes can be hijacked by cancer. Additionally, she will receive structured Applied Biostatistics training through formal coursework at Harvard Catalyst. Genes, which are the instruction manual of the cell, are turned “on” (activated) or “off” (repressed) to different extents depending on the characteristics and needs of the cell. During normal development, two groups of proteins balance gene activation and repression. The SMARCB1 gene writes the instructions for a member of the BAF complex of proteins, which together promote the activation of many genes. The gene activation promoted by the BAF complex is balanced by gene repression controlled by a group of proteins called the polycomb repressive complex 2 (PRC2). Alterations in this balance of gene activation and repression leads to abnormal development, and frequently promote cancer. Twenty percent of all cancers have mutations in the BAF complex, and advancing knowledge about this group of proteins has broad implications for many cancer types. Part of the project will involve testing whether an oral medication called tazemetostat (also known as EPZ-6438), which inhibits PRC2 and is currently under clinical trials in patients for the treatment of other cancers due to BAF complex mutations, could also be potentially therapeutic for patients with SMARCB1 mutant meningiomas. The impact of tazemetostat on meningioma cell growth and survival will be studied in the culture dish. However, if there is evidence that this medication inhibits meningioma cell growth in the culture dish, there is the potential for immediate transition to clinical trials in patients with SMARCB1 mutant meningiomas, as the medication is already known to be safe in humans and is being used in clinical trials for other cancers. By focusing on how specific alterations in SMARCB1 shift the balance between the BAF complex and PRC2 and lead to meningioma formation, the long-term goal is to not only improve treatment options for patients with meningiomas (e.g., provide a medication option and avoid neurosurgery) but also provide new insights into BAF complex function that can help patients with many cancer types. This will enhance mission readiness, health, and quality of life for Service members and Veterans for several reasons. Firstly, SMARCB1 mutations are enriched in atypical meningiomas, which have a more aggressive clinical course compared to histologically benign meningiomas. Secondly, SMARCB1 mutant meningiomas preferentially grow in the anterior midline (falx) of the frontal lobe of the brain. Both tumor growth and neurosurgical resection of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010716
Entities
People
- Victoria Clark
Organizations
- United States Army
- Whitehead Institute