Medulloblastoma: Molecular understanding, treatment evolution, and new developments

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Abstract

Medulloblastoma (MB) is the most common childhood malignant brain tumor, accounting for approximately 20% of all pediatric central nervous system tumors. Current standard treatments involving surgical interventions followed by craniospinal irradiation and adjuvant chemotherapy have severe motor and cognitive defects. Therefore, individualized treatment regimens with reduced toxicity designed according to the presence of specific oncogenic ‘driver’ genes are urgently demanded. To this end, recent genetic and epigenetic findings have advanced the classification of MB into the international consensus of four distinct MB molecular subgroups (WNT, SHH, Group 3, and Group 4) based on their respective molecular and histopathological characteristics. More recent studies have indicated that up to seven molecular subgroups exist in childhood MB. Moreover, studies on the inter- and intra-tumoral features of the four subgroups revealed that each subgroup contains variant subtypes. These results have greatly helped risk stratification of MB patients at diagnosis and significantly improved clinical treatment options. Herein, we highlight the recent advances and challenges associated with MB classification, and the development of therapeutic treatments targeting novel subgroup-specific molecular and epigenetic factors, especially those in the SHH-driven MB tumors.

Introduction

Medulloblastoma (MB) is a high-grade malignancy that was initially described in 1925 as a distinct series of childhood cerebellum tumors. MB dominantly occurs in infancy (ages less than 3 years) and childhood (ages younger than 16 years) and now represents the most common childhood malignant brain tumor accounting for nearly 20–30% of all pediatric central nervous tumors in children (Ostrom et al., 2015; Pui, Gajjar, Kane, Qaddoumi, & Pappo, 2011).

MB generally occurs in the posterior fossa, making its diagnosis and treatment much challenging and often delayed. In the 1930s, surgical intervention was the only treatment option for MB; however, the immediate post-operative mortality rate was found higher than 30% (Millard & De Braganca, 2016). Until the 1950s, craniospinal irradiation was introduced as an adjuvant treatment following surgical resection and showed improved survival rates. Unfortunately, serious motor and cognitive adverse effects, including neurocognitive impairment, secondary malignancies, and endocrine dysfunction were observed in younger patients (Millard & De Braganca, 2016; Paterson & Farr, 1953). Since the 1970s, non-specific cytotoxic chemotherapy was introduced in combination with surgery and/or radiation (Fig. 1) (Millard & De Braganca, 2016; Tait, Thornton-Jones, Bloom, Lemerle, & Morris-Jones, 1990). Currently, cytotoxic chemotherapy combined with radiation continues to be used as the standard therapy for MB. However, the long-term use of these therapeutic regimes has shown to induce substantial toxic damages, most notably in developing young patients. The inability of the therapy to recognize both the inter- and intra-tumoral heterogeneity of MB subgroups and the lack of clinical biomarkers to stratify patients, are the major drawbacks underlying the adverse effects (Jakacki et al., 2012; Lannering et al., 2012).

Section snippets

Early classification of MB: From morphological to histological

When MB was first described in the 1930s, it was classified as a large subgroup of malignant invasive embryonal tumors of the cerebellum based on similar morphology with densely packed cells. Metastases of MB barely occur outside the central nervous system, but have been occasionally observed in the bone marrow, lymph nodes, and viscera (Eberhart, Cohen, Tihan, Goldthwaite, & Burger, 2003). In the 1980s the World Health Organization (WHO) classified MB into four main histologic types, namely,

Treatment challenges and current available therapies

Since MB tumors are located in the posterior fossa, early diagnosis and treatment are difficult and metastases often occur at diagnosis, which are the leading cause of mortality, especially for those high-risk MB patients. Maximal surgical resection followed by radiation and chemotherapy is the current standard therapy. However, >25% of patients experience cerebella mutism, dysarthria and neurocognitive disorders after surgical operation, and the adjuvant craniospinal radiotherapy and

Concluding remarks and future perspectives

MB is the most common and yet highly heterogeneous childhood malignant brain tumor. Since MB occurs in the posterior fossa, discrimination is difficult and 70–80% of MB patients are diagnosed before metastatic dissemination survive, thus making treatment of this disease even harder (Quinlan & Rizzolo, 2017). Recent application of new genomic and epigenetic profiling technologies has revolutionized the classification of MB from strictly morphology-based to molecular and epigenetic

Declaration of Competing Interest

The authors declare that there are no conflicts of interest.

Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (Grants 81773565). Supporting grants from the Key Program of the Frontier Science (Grant 160621) of the Chinese Academy of Sciences, and the Strategic Leading Project A on Precision Medicine of the Chinese Academy of Sciences (XDA12020374, XDA12020226, XDA1250400) are also highly appreciated. A start-up grant to the Research Laboratory of Medicinal Chemical Biology & Frontiers on Drug Discovery (RLMCBFDD) from

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