**2. Molecular subgroups of medulloblastoma**

treated with a combination of chemotherapy followed by radiation, although radiation therapy alone has been used [15, 17, 18]. Multiple protocols exist for the chemotherapeutic treatment of medulloblastoma. One chemotherapeutic regimen includes treatment with a combination of vincristine, cisplastin, lomustine, and cyclophosphamide alongside radiation therapy over about a 1-year period [15]. High-risk or unresectable tumors are also treated with chemora‐ diation. Infants (<3 years old) are typically not treated with radiation owing to intolerability

Risk stratification of medulloblastoma patients has improved cure rates for high-risk cases and limited radiation therapy exposure in treatment regimen for standard-risk patients, thereby reducing side effects. Nevertheless, even with improved cure rates for patients, long-term sequelae of treatment remain a concern. Radiation therapy has been associated with long-term neurocognitive deficits, cytopenias, opportunistic infections, and secondary malignancies [15, 19]. Children are especially sensitive to the adverse effects of radiation therapy, and as such

Long-term chemotherapy too has known side effects that have been described extensively elsewhere and include neurocognitive impairment, hearing loss, endocrine perturbations, cardiac and respiratory conditions, and secondary malignancies [15, 20]. Moving forward, further studies need to be performed to optimize current treatment or to identify new therapeutics to minimize side effect profile. Classification of medulloblastoma subgroups, for instance, focuses research toward drug targets within molecular pathways driving these

In one trial of pediatric medulloblastoma, 10-year event free survival (EFS) and overall survival (OS) rates were 75 and 80%, respectively, for kids with standard-risk medulloblasto‐ ma treated with radiation followed by chemotherapy [21]. In another trial, 5-year EFS ranged from 65 to 70% in patients who received both chemotherapy and radiation following tumor resection [13]. Treatment with radiation therapy alone had survival rates 50–65% even with

In comparison to pediatric medulloblastoma literature, studies assessing the treatment of adult medulloblastoma are rare. One retrospective study of adult medulloblastoma treated with chemotherapy and craniospinal radiation identified a 4-year EFS of 68% [18]. Other studies

Relapses most likely occur within the first 2 years of diagnosis, with one-third occurring within the first 3–5 years [21]. Earlier relapses are more likely to be associated with metastatic disease [21], while later relapses (>5 years after diagnosis) were more likely to be related to local disease. The posterior fossa is the most common site of relapse. Relapses must be distinguished from secondary tumors. Secondary tumors can occur following radiation, either at sites of prior irradiation or at extracranial sites near sites of primary radiation (thyroid, bone, etc.). One study identified a 4.2% 10-year cumulative incidence of secondary tumors follow‐

radiation doses for treatment are lower for pediatric than for adult patients [15].

subgroups. These subgroups are described in detail below.

of side effects.

384 Neurooncology - Newer Developments

**1.4. Prognosis**

higher dose radiation [21, 22].

have identified survival rates of 40–80% [23].

The World Health Organization has subdivided medulloblastoma into five distinct histopa‐ thologic categories [24]: classic, desmoplastic/nodular, medulloblastoma with excessive nodularity, anaplastic medulloblastoma, and large cell medulloblastoma (**Figures 2** and **3**). Certain histological subtypes predominate patient age groups: 71% of pediatric cases classi‐ fy as classic medulloblastoma, whereas 57% of infant cases exhibit desmoplastic/nodular histology [25]. Large cell and anaplastic medulloblastomas are associated with a poor prognosis, whereas desmoplastic/nodular medulloblastomas usually demonstrate an excel‐ lent outcome [25].

**Figure 2.** Medulloblastomas are grouped histologically or molecularly. Left image shows MRI of a pediatric patient with a classical medulloblastoma. Right image shows MRI of an infant with medulloblastoma with extensive nodulari‐ ty. Copyright © 2014 Faculty of 1000 Ltd, from *Advances in managing medulloblastoma and intracranial primitive neuroectodermal tumors* (Adamski, Ramaswamy, Huang and Bouffet, F1000Prime Rep. 2014).

In addition to histological categories, retrospective molecular diagnostics have additionally allowed for medulloblastoma to be subdivided into four molecular subgroups (**Table 1**). The most well understood of these four subgroups are those medulloblastoma variants that involve the sonic hedgehog pathway (30% of patients with medulloblastoma and 60% of adults) and those involving the Wnt pathway (10% of all patients with medulloblastomas and 15% of adults) [26]. Molecular subgrouping may inform chemotherapy regimen, especially in light of emerging research about potential drug targets within involved molecular pathways.

**Figure 3.** Histological slides stained with hematoxylin and eosin of medulloblastomas showing heterogeneity across patient tissue samples. Images obtained with permission from Dr. Kay Ka Wai Li (Prince of Wales Hospital, Depart‐ ment of Anatomical and Cellular Pathology, The Chinese University of Hong Kong).

#### **2.1. Wnt pathway medulloblastoma**

Wnt-type medulloblastoma is characterized by enhanced Wnt-β-catenin pathway activation [5] and tends to show classic histology rather than the poorer prognoses anaplastic or large cell type histology [6]. Among the medulloblastoma molecular subgroups, Wnt medulloblastoma is the least common, occurring in 10–15% of medulloblastomas [27]. It affects males 1.5 times more than females [6] and occurs rarely in infants (<3 years old). For reasons that have yet to be elucidated, medulloblastoma tumors carrying Wnt mutations carry a better prognosis than other subtypes. In fact, meta-analysis of medulloblastoma subgroups found an overall 10-year survival rate of 95% in children with Wnt medulloblas‐ toma and 100% 5-year survival rate among adult Wnt medulloblastoma [6].

#### *2.1.1. Molecular basis of Wnt medulloblastomas*

In addition to histological categories, retrospective molecular diagnostics have additionally allowed for medulloblastoma to be subdivided into four molecular subgroups (**Table 1**). The most well understood of these four subgroups are those medulloblastoma variants that involve the sonic hedgehog pathway (30% of patients with medulloblastoma and 60% of adults) and those involving the Wnt pathway (10% of all patients with medulloblastomas and 15% of adults) [26]. Molecular subgrouping may inform chemotherapy regimen, especially in light of

emerging research about potential drug targets within involved molecular pathways.

**Figure 3.** Histological slides stained with hematoxylin and eosin of medulloblastomas showing heterogeneity across patient tissue samples. Images obtained with permission from Dr. Kay Ka Wai Li (Prince of Wales Hospital, Depart‐

Wnt-type medulloblastoma is characterized by enhanced Wnt-β-catenin pathway activation [5] and tends to show classic histology rather than the poorer prognoses anaplastic or large cell type histology [6]. Among the medulloblastoma molecular subgroups, Wnt medulloblastoma is the least common, occurring in 10–15% of medulloblastomas [27]. It affects males 1.5 times more than females [6] and occurs rarely in infants (<3 years old).

ment of Anatomical and Cellular Pathology, The Chinese University of Hong Kong).

**2.1. Wnt pathway medulloblastoma**

386 Neurooncology - Newer Developments

All medulloblastomas with heightened nuclear staining of β-catenin are grouped into Wnttype. β-Catenin is a key promoter of the Wnt pathway, an evolutionarily conserved pathway involved in cellular homeostasis and embryogenesis. The pathway is involved in central nervous system development; indeed, derangements of Wnt signaling have been described in diseases of the CNS, including neural tube defects, Williams syndrome, Alzheimer's disease, and schizophrenia [28].

The Wnt pathway classifies into the canonical pathway and two separate noncanonical pathways. The noncanonical Wnt pathways appear to be independent of β-catenin. The canonical pathway is β-catenin dependent and is characterized by interaction of a Wnt ligand with the extracellular domain of Frizzled, a G-protein-coupled receptor. This interaction results in accumulation of intracellular β-catenin, promoting downstream gene activation [29, 30]. Multiple genes and proteins have been identified as regulatory factors for this pathway. β-Catenin is an unstable protein, and in the absence of Wnt ligand, it is broken down by a degradation complex composed of multiple proteins, the tumor suppressor protein APC and the scaffolding protein AXIN [31] are among them.

Ninety percent of the time, Wnt medulloblastoma is driven by mutation of β-catenin (*CTNNB1*), resulting in increased activation of MYC and MYCN oncogenes [5, 27]. A num‐ ber of other frequently mutated genes have been identified in Wnt medulloblastoma [5, 27].

Alongside other evolutionarily conserved pathways [31] including the SHH and Notch pathways, the Wnt pathway has also been implicated in the development of cancer stem cells (CSCs), a subgroup of cancer cells defined by their pluripotency and capacity for selfrenewal [29, 31]. The identification of cancer stem cells as a subgroup of pluripotent selfrenewing cancer cells has led to the theory that they may be necessary for tumorigenesis. Aberrations in evolutionary conserved pathways, including the Wnt pathway, are frequent‐ ly identified in cancer stem cells. The Wnt pathway therefore is an attractive means for targeting cancer stem cells, particularly in malignancies that are known to overexpress Wnt.

#### *2.1.2. Drug targets in Wnt medulloblastoma*

A number of molecules that interact with the Wnt pathway are currently being investigated as potential antitumor therapies in both preclinical studies and clinical trials. Tankyrase inhibitors have been identified that lead to downstream degradation of β-catenin [29]. JW55, a novel tankyrase inhibitor, has been shown in mice studies to reduce tumor development and colorectal cancer cell growth [32]. Inhibitors of Dishevelled, a protein that promotes down‐ stream Wnt signal transduction, have also been shown to inhibit downstream Wnt signaling [33].

Interestingly, known nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to have anti-Wnt pathway activity, possibly explaining in part their antineoplastic properties [27, 34, 35]. *In vitro* studies of colon cancer cells have shown that the NSAID sulindac inhibits canonical Wnt pathway activity via inhibition of cGMP hydrolysis [27]. Sulindac may also affect the Wnt pathway by affecting Dishevelled [34]. Celecoxib and diclofenac have been shown to decrease Wnt pathway signaling in *in vitro* glioblastoma cells [36]. Aspirin too affects the Wnt pathway [37]; in one study, aspirin diminished tumorigenesis in intestinal cells. The possible mechanism for aspirin in this study was downregulation of the expression of *PPARδ*, a growth and antiapoptotic promoting transcription factorthat is a direct product of the Wnt pathway [38].

There are a number of ongoing trials using novel agents targeting the Wnt pathway. These agents include PRI-724, designed by Prism BioLab and which blocks the interaction of βcatenin with cotranscriptional coactivator CBP [29, 31]. A Phase I clinical on the molecule LGK-794, a porcupine inhibitor that inhibits Wnt protein secretion, is currently recruiting patients and will assess the safety profile in patients who carry malignancies that are depend‐ ent on Wnt ligands [29, 31]. It is important to note that these Wnt pathway-targeting com‐ pounds have not been tested in medulloblastomas, which would be the next direction for assessing their efficacy in Wnt medulloblastoma. However, although the Wnt pathway is a potential target for future medulloblastoma therapies, some authors have described poten‐ tial theoretical barriers to the utilization of Wnt-targeted therapy in malignancy [28]. First, the Wnt pathway is crucial to organogenesis and homeostasis, begging the question as to whether altering the Wnt pathway may be detrimental to these processes. Second, some have contest‐ ed the assumption that Wnt pathway antagonism would be desirable as anticancer therapy, given that the Wnt pathway is involved in neural regeneration after brain injury (such as surgery). The ongoing clinical trials using therapies targeting the Wnt pathway will help to better elucidate the safety and viability of targeting this pathway.


**Table 1.** Summary of key aspects of the four molecular subgroups of medulloblastoma.
