Macrophages in SHH Subgroup Medulloblastoma Display Dynamic Heterogeneity That Varies With Treatment Modality
Medulloblastoma (MB) is the most common malignant brain tumor of childhood, accounting for more than 20% of pediatric brain tumors. It is biologically heterogeneous, comprising four major molecular subgroups: WNT, sonic hedgehog (SHH), group 3, and group 4. Given the high-grade nature of this tumor type, treatment is aggressive and involves surgical resection, chemotherapy, and radiation. MB are radiosensitive, but radiation can lead to severe neurological side effects, which limits its use in young children. Prognosis depends on multiple characteristics of the tumor and is worse for patients in the high-risk stratification. Overall survival for these patients has been estimated to be from 50% to 75% (Bouffet, 2021).
Recent identification of activating pathways in MB provide opportunities for molecular-targeted therapy. Inhibitors of the SHH pathway, such as GDC-0449 (vismodegib), have shown remarkable efficacy in treating murine SHH-MB and human patients in clinical trials (Robinson et al., 2015; Romer et al., 2004). However, development of resistance to GDC-0449 remains a concern, and the drug is contraindicated in children under the age of 10 because of its negative impact on bone growth (Dijkgraaf et al., 2011; Gajjar et al., 2013; Robinson et al., 2017). Hence, there is an urgent need for novel therapeutics in high-grade MB.
We thank Drs. Weixia Liu and Stephen Pickup for their assistance with MRI, Dr. Khayrullo Shoniyozov and Denisa Goia for their assistance with radiation, Drs. Jay Storm and Adam Resnick for their dedication to the generation of human patient date used in the OpenPBTA project, Dr. Mateusz Koptyra for his helpful suggestions, and Dr. Chi Van Dang for his invaluable insight.