Meningiomas are the most prevalent form of brain cancer, and affect over 170,000 individuals in the United States annually. Mutations in subunits of the Polybromo-associated BAF (PBAF) complex have previously been described in whole-exome sequencing studies, however the full extent of this complex?s involvement in meningioma remains unknown. The PBAF complex is implicated in many forms of neoplasia, and within each tumor type, the loss of several independent subunits is sufficient for oncogenesis. This pattern suggests that additional subunits may be involved as oncogenic drivers in meningioma.
In Aim 1 of this study, a targeted genomic screen of PBAF subunits will be performed in a large cohort of tumor samples with detailed clinical annotation. The results will elucidate the full involvement of this complex in meningioma, and identify patient populations that might benefit from precision therapies.
In Aim 2, the Polycomb Repressive Complex 2 (PRC2) will be investigated as an oncogenic mechanism and therapeutic target in these tumors. The antagonistic relationship between PBAF and PRC2 is a well-established, and evidence from other cancers suggest that PBAF subunit mutations drive cancer by concomitant activation of PRC2. Inhibitors of PRC2 are capable of arresting tumor growth in several models of PBAF-driven malignancies, and may also be efficacious in meningioma. However, before this approach can be considered in patients, experiments are needed to validate the role of PRC2 in meningioma and the effectiveness of therapeutics that target this pathway. PBAF mutant primary meningioma cells will be used to test the dependency of these tumors on PRC2 activation, based on their response to a potent PRC2 inhibitor. This approach will also establish a proof-of-principle for use of pharmacologic inhibitors in human patients. The downstream genomic targets of this pathway will be further interrogated using H3K27me3 ChIP-seq, a specific mark for PRC2 activity. Results will be correlated with gene expression from the same tumors to identify dysregulated loci in mutant tumors.

Public Health Relevance

Meningiomas are the most common type of brain tumor, and a subgroup of these lesions arise due to genetic mutations affecting the Polybromo-associated BAF (PBAF) complex. Other cancers associated with PBAF mutations have been treated with inhibitors of the Polycomb Repressive Complex 2 (PRC2), which is normally antagonized by PBAF and may be responsible for the oncogenic effects of PBAF subunit mutations. Understanding the extent of involvement of PBAF in meningioma, as well as the response of meningioma cells to PRC2 inhibitors, will expedite the use of these therapies in patients and reduce the need for invasive neurosurgical procedures.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30CA213666-02
Application #
9628645
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Damico, Mark W
Project Start
2018-02-01
Project End
2022-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Graduate Schools
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520