There is an urgent need to develop novel therapies for patients with medulloblastoma (MB), the most common malignant central nervous system (CNS) tumor in children. Current treatments include surgery, radiotherapy, and chemotherapy and result in 5-year survival rates of 40-90% depending on subtype. Moreover, children suffer important morbidity secondary to treatment, including neurological, intellectual and physical disabilities. The overall purpose of the present project is to investigate the role of the Brain-specific Angiogenesis Inhibitor 1 (BAI1) in cerebellar development and susceptibility to transformation, and explore new therapies for MB based on the related mechanisms. BAI1 is an orphan seven transmembrane G protein-coupled receptor (GPCR) specifically expressed in the brain, and belonging to the adhesion-type sub-family. Our new preliminary data show that BAI1 expression is significantly reduced in patients with MBs, and the promoter is epigenetically silenced, suggesting that BAI1 loss may facilitate MB formation. To test this in the physiological setting, we generated Bai1 knockout (KO) mice and found haploinsufficiency of Bai1 dramatically accelerates MB tumorigenesis in Ptch1+/- transgenic mouse models of MB, the first demonstration that a reduction in Bai1 dosage can promote MB formation in vivo. Interestingly, we detected enhanced Gli1/2 expression and a thicker external granule layer (EGL) during early postnatal cerebellum development in the Bai1 KO mice. Therefore, our preliminary studies link BAI1 with cerebellar development and neoplastic transformation. Based on these results, we hypothesize that BAI1 is a tumor suppressor in the cerebellum and that restoration of its expression with epigenetic therapy may represent a novel therapeutic intervention for MB. To test our hypothesis, we propose the following aims: (i) determine whether Bai1 loss accelerates MB formation in mice through abnormal activation of a growth-signaling pathway in the developing cerebellum, (ii) determine how BAI1 restoration in human MB cells can inhibit their growth, and alter their tumorigenic properties, and (iii) define the mechanisms of BAI1 inactivation in MB, and determine whether epigenetic reactivation of BAI1 expression has therapeutic effects in vivo. These studies are important as they increase our knowledge about developmental neurobiology in the CNS, and may lead to the development of novel therapeutic approaches for patients with medulloblastoma.

Public Health Relevance

We want to study the tumor suppressor function of the Brain-specific Angiogenesis Inhibitor (BAI1) in brain development. We found that loss of Bai1 expression in mice is associated with abnormal development in the cerebellum and medulloblastoma formation, a highly malignant brain tumor in children. The knowledge derived from these studies may lead to the development of novel therapeutics for brain cancer through the restoration of the BAI1 tumor suppressor pathway function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS096236-05
Application #
10179178
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
2020-07-01
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Zhu, Dan; Osuka, Satoru; Zhang, Zhaobin et al. (2018) BAI1 Suppresses Medulloblastoma Formation by Protecting p53 from Mdm2-Mediated Degradation. Cancer Cell 33:1004-1016.e5
Ng, Terry Fei Fan; Dill, Jennifer A; Camus, Alvin C et al. (2017) Two new species of betatorqueviruses identified in a human melanoma that metastasized to the brain. Oncotarget 8:105800-105808
Osuka, Satoru; Van Meir, Erwin G (2017) Overcoming therapeutic resistance in glioblastoma: the way forward. J Clin Invest 127:415-426
Bolyard, Chelsea; Meisen, W Hans; Banasavadi-Siddegowda, Yeshavanth et al. (2017) BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection-Implications for Oncolytic Viral Therapy. Clin Cancer Res 23:1809-1819
Aust, Gabriela; Zhu, Dan; Van Meir, Erwin G et al. (2016) Adhesion GPCRs in Tumorigenesis. Handb Exp Pharmacol 234:369-396
Morrissy, A Sorana; Garzia, Livia; Shih, David J H et al. (2016) Divergent clonal selection dominates medulloblastoma at recurrence. Nature 529:351-7
Zhu, Dan; Van Meir, Erwin G (2016) BAI1: from cancer to neurological disease. Oncotarget 7:17288-9
Kalinina, Juliya; Ahn, Jun; Devi, Narra S et al. (2016) Selective Detection of the D-enantiomer of 2-Hydroxyglutarate in the CSF of Glioma Patients with Mutated Isocitrate Dehydrogenase. Clin Cancer Res 22:6256-6265
Ramaswamy, Vijay; Hielscher, Thomas; Mack, Stephen C et al. (2016) Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol 34:2468-77
Thompson, Eric M; Hielscher, Thomas; Bouffet, Eric et al. (2016) Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis. Lancet Oncol 17:484-495