Medulloblastoma is one of the leading cancers in pediatric patients. It is an embryonal tumor that originates from the cerebellum or posterior fossa. It is one of the most common cancers in children, and 40% cases were diagnosed below the age of 5 years. Data analysis performed on surveillance, epidemiology and end-results (SEER) for 9 registries suggested that 1372 cases were diagnosed in the period 1973 to 2007. The associated risk factors for the development of medulloblastoma are unknown. Pathophysiology can be best understood with the help of cellular signaling pathways which includes signaling pathways like SHH Signaling, Wnt Signaling and Notch Signaling. Till date, no immune-oncology product has been approved by FDA for this indication. Some available immune-oncology products are under investigation in clinical trials phase I to III. The complete perspective of immunotherapy treatment has not been realized and utilized.

Keywords: Medulloblastoma, Sonic Hedgehog (SHH) signaling, Wnt signaling, ErbB signaling, C-myc signaling, IGF/PI3K signaling and nd notch signalling, Desmoplastic/nodular type, Medulloblastoma with extensive nodularity, Large-cell variant, Anaplastic medulloblastoma a, Environmental factors, Irradiation and radiation, Viral infection, Genetic alteration, Monoclonal antibodies (mAbs), SHH inhibitors, Tyrosine kinase autologous stem cell transplantation and autologous stem-cell rescue

Abbreviations: AHSCR: Autologous Stem-Cell Rescue; APC: Adenomatous Polyposis Coli; CBTRUS: Central Brain Tumor Registry of the United States, CSF: Cerebrospinal Fluid; EGFR: Epidermal Growth Factor; FDA: Food and Drug Administration; GSK3-β: Glycogen Synthase Kinase 3-β; HDCT-AHSCR: High-Dose Chemotherapy with Autologous Stem Cell Rescue; Hh: Hedgehog; IRS-1 Insulin Receptor Substrate-1; LRP: Lipoprotein Receptor-Related Protein; LEF: Lymphoid Enhancer Factor; mAbs: Monoclonal Antibodies; MAPK: Mitogen-Activated Protein Kinase; OSR: Overall Survival Rate; PDGFRB: Platelet-Derived Growth Factor Receptor B, PI3K: Phosphatidylinositol 3-Kinase; PKB: Protein Kinase B; PTCH1: Gene Patched 1; mTOR: Mammalian Target of Rapamycin, SEER: Surveillance, Epidemiology and End-Results; SHH: Sonic Hedgehog Signaling; TCF: Transcription Factors T-Cell Factor, US: United States

INTRODUCTION

Medulloblastoma is an embryonal tumor that originates from the cerebellum or posterior fossa [1]. Cerebrospinal fluid (CSF) plays an important role, in terms of metastasizing to different sites in the brain and spine. Infratentorial tumors are invasive and grow rapidly in comparison to other tumors [2].

Medulloblastoma is one of the most common cancers in children and 40% cases were diagnosed below the age of 5 years [3]. It accounts for less than 2% of adult brain tumors and approximately 18% of pediatric brain tumors. The median age for medulloblastoma is approximately 7 years in children and 25 years for adults [4].

Data analysis performed on surveillance, epidemiology and end-results (SEER) for 9 registries suggested that 1372 cases were diagnosed in the period 1973 to 2007. As per the CBTRUS statistical report in 2005-2009, 2,617 cases of embryonal tumors was identified [5].

Statistical representation of data in accordance to gender, race and Hispanic ethnicity

A study conducted by Padovani et al. [6] and similar studies in adults, stated that 5 years and 10 years overall survival rate (OSR) was 72% and 55% respectively, in 2004.There is predominance of male over female in respective ratio of 1.33:1, with higher incidence observed in between the age of 3 to 20 years [7] (Table 1).

Etiology/predisposing factors

The associated risk factors for the development of medulloblastoma are unknown. Familial history can increase the chances of development of brain tumor.

Environmental factors: Diet and vitamins have shown some effects due to the key role of nitrosamines, oxidants and antioxidants. It is not clearly defined, but it might predispose to pediatric brain tumor [8]. Some studies show effects of exposure to carcinogens as a leading cause of pediatric brain tumor. Evidence revealed that the father getting exposed to carcinogens prior to conception and the mother at the time of maternity will damage DNA and predispose to cancer [9].

Irradiation and radiation: It has been observed that children who are constantly exposed to radiations have higher chances of developing childhood brain tumors. In a study, it was reported that the lesser exposure to strontium-90 after the nuclear power plants ceased to operate, led to lower incidences of brain tumor in children [10,11].

Viral infection: Few studies suggested a strong relationship between human neurotropic polyoma virus, i.e., JC virus and medulloblastoma. Viral protein plays an important role in the binding efficacy, interference to tumor suppressor activity and regulation of protein like p53 and Rb [12]. Exposure to measles immunization and SV40 shows link to the development of medulloblastoma [13].

Genetic alteration: Various genetic disorders act as important predisposing factor for the development of medulloblastoma. These syndromes along with their genes and chromosomal locations have been mentioned in Table 2.

Pathophysiology and molecular basis

Pathophysiology can be best understood with the help of cellular signaling pathways.

Figure 1 explains the various signaling pathways associated with the pathogenesis of medulloblastoma.

Sonic Hedgehog (SHH) signaling

Gene Patched 1 (PTCH1), a tumor suppressor, located on 9q22.3 chromosomal location encrypts for Hedgehog proteins’ transmembrane surface receptor. This pathway is associated with the progression of external granular layer of the cerebellum. Purkinje cells produce SHH, which binds to PTCH1 receptor and makes the smoothened (SMO) free from inhibition by activating the proliferation of precursors of cerebellar granule cell. It also activates the Gli family of transcription factors. In medulloblastoma, BMI1 is over-expressed. This disrupts the normal regulation of signaling pathways like Rb and p53 [14].

Wnt signaling

A protein complex is formed by adenomatous polyposis coli (APC) in association with β-catenin (CTNNB1), axin 1 (AXIN1) and glycogen synthase kinase 3-β (GSK3-β). In case of Turcot’s syndrome, APC is germ line mutated and is the predisposing factor for the development of medulloblastomas [15].

Wingless (WNT) ligand binds to a receptor complex, which includes seven transmembrane Frizzled (FZ), serpentine receptor and low density lipoprotein receptor-related protein (LRP). CTNNB1 is prevented from phosphorylation by glycogen synthase kinase-3β (GSK-3β) and is translocated to the nucleus. Upon activation, a downstream effect of β-catenin is observed and deprivation is followed by TCF (Transcription Factors T-cell Factor)/LEF (Lymphoid Enhancer Factor) interaction with activation of transcription of Wnt targets gene (c-Myc, cyclin D1 and AXIN2) [16].

Survivin, an apoptosis inhibitor is also over-expressed in the presence of activation of Wnt signaling pathway. SOX4 and SOX11 are over-expressed as well and are linked to medulloblastoma [15].

Notch signaling

In Human, 4 types of NOTCH receptor have been identified. Notch, heterodimeric receptor, is a single transmembrane protein. NOTCH 2 is overexpressed in case of medulloblastoma. Extracellular domain and cytoplasimc domain contains different binding efficacy. Cytoplasmic domain contains domain like RAM, a transcription transactivation, two nuclear localization signals, six CDC10 repeats and a PEST sequence. Extracellular binding helps in ligand binding and contains epidermal growth factor (EGFR) like repeats. In the absence of ligand binding, extracellular domain will impede signaling. Once NOTCH binds to ligands Jagged (JAG-1, JAG-2) and Delta-like (DLL-1, DLL-2, DLL-3) family members, release of Notch intracellular domain (NCI) and translocation to the nucleus takes place.[16] NCI interacts with DNA binding proteins (CBF1), which in turn activate the loop-helix transcription factors HES1 and HES5. HES1 forms transcriptional repressor complexes with FOXG1 which negatively regulates the differentiation of neural progenitor cells [15].

ErbB signaling

ErbB include four receptors (ErbB1-ErbB4) and a variety of ligands and neroregulins. They belong to tyrosine kinase family. ErbB4, CYT1 isoform, is over-expressed in tumor, which activates anti-apoptotic phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)/AKT signaling. ErbB2 gene is located on 17q11.2-q12 chromosome and is regarded as a prospective medulloblastoma oncogene. The ErbB ligand, NRG1-β is expressed by ErbB2 and ErbB4 results in disease progression, while C-myc is the leading target.

C-myc signaling

C-myc is linked to the activation of the different signaling pathways like SHH and Wnt pathways, translocations, viral insertion, genomic amplification and activating mutations. C-myc binds to JPO2 protein, which can activate C-myc transformation. It is related to metastatic medulloblastoma. N-Myc is linked to SHH signaling pathway. PI3K prevents the degradation of N-Myc and in turn, enhances the effects of IGF/PI3K signaling pathway. This process explains the development of medulloblastoma associated with SHH pathway.

IGF/PI3K signaling

IGF-1 receptor (IGF-1R) protein (e.g. insulin receptor substrate-1 (IRS-1), PI3K, AKT/PKB, Erk-1 and Erk-2) and activated phosphorylated form of IGF-1R are over-expressed, in case of medulloblastoma. Inhibition of dephosphorylation of GSK3-β and IGF-1R are important for the management of medulloblastoma by reducing tumor growth. IGF-1R signaling pathway can lead to the activation of AKT, PI3K, ras/MAPK (mitogen-activated protein kinase) signaling. In case of metastatic medulloblastoma, up-regulation of ras/MAPK pathway and platelet-derived growth factor receptor B (PDGFRB) are key factor [17].

CELLS OF ORIGIN

Activation of different signaling pathways in different medulloblastoma subtypes suggest that medulloblastomas have different origins. There are four types of medulloblastoma identified, based on the following molecular and genetic aspects as well as clinical and prognostic features.

1)       Desmoplastic/nodular type

2)       Medulloblastoma with extensive nodularity

3)       Large-cell variant

4)       Anaplastic medulloblastoma

IMMUNOTHERAPY

Monoclonal antibodies (mAbs)

Non-FDA approved monoclonal antibodies: There is no FDA approved monoclonal antibody as an immunotherapy for medulloblastoma. However, Bevacizumab is under clinical trials for the management of medulloblastoma as mentioned below in Table 3.

 SHH inhibitors:

Non-FDA approved SHH inhibitor: Currently no SHH inhibitor is approved by FDA for medulloblastoma. However, some SHH inhibitors that are under clinical trials are mentioned in Table 4. The secreted SHH ligand generate the signal by smoothened (SMO) receptor and helps in the proliferation of neural precursor cells.

Tyrosine kinase inhibitors

Non-FDA approved tyrosine kinase inhibitors: Currently, no tyrosine kinase inhibitor is approved by FDA for medulloblastoma. However, the kinase inhibitors under clinical trials are mentioned in Table 5.

Autologous stem cell transplantation

Autologous stem-cell rescue: The procedure of high-dose chemotherapy with autologous stem cell rescue (HDCT-AHSCR) has been one of the successful treatment modalities in medulloblastoma. AHSCR also restores the suppression of the process of hematopoiesis, which is limited by the dose of the chemotherapy [24].

A COG trial has been done using the combination of chemotherapy and peripheral stem cell transplant. This COG trial is open for children aged 3 years or younger, on being diagnosed with high-risk disease, which is defined as those with disseminated and/or sub-totally resected tumors or those younger than 8 months with otherwise standard-risk disease. Patients with cortical primitive neuroectodermal tumors or pineoblastomas are also eligible. This study is evaluating chemotherapy as given in the completed COG study COG-99703, which used multi-agent chemotherapy followed by thiotepa-based, higher-dose, marrow-ablative chemotherapy and peripheral stem cell rescue, and randomly assigns patients to treatment with or without intravenous high-dose methotrexate [25].

COX-2 inhibitors

Non-FDA approved COX-2 inhibitors: Currently, no COX-2 inhibitor is approved by FDA for medulloblastoma. However, the COX-2 inhibitors under clinical trials are mentioned in Table 6.

mTOR inhibitors

Non-FDA approved mTOR inhibitors: Currently, no mTOR inhibitor is approved by FDA for medulloblastoma. However, the mTOR inhibitors under clinical trials are mentioned in Table 7.

CONCLUSION

Medulloblastoma is one of the leading cancers in pediatric patients. Pathophysiology includes signaling pathways like SHH Signaling, Wnt Signaling and Notch Signaling. Apart from that, chromosome 17, p53, 17p gene, RENKCTD11, MnT and duplication of genes on 17q are few leading causes for the pathogenesis of medulloblastoma. Till date, no immune-oncology product has been approved by FDA for this indication. Some available immune-oncology products are under investigation in clinical trials phase I to III. The complete perspective of immunotherapy treatment has not been realized and utilized. Proper pre-clinical and clinical designs are the important pillars in understanding the future of immunotherapy in treating cancer patients.

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