|Year : 2020 | Volume
| Issue : 3 | Page : 175-182
Medulloblastoma under siege: Genetic and molecular dissection concerning recent advances in therapeutic strategies
Zeal D Rawal1, Vinal A Upadhyay1, Dipak D Patel2, Trupti I Trivedi1
1 Clinical Carcinogenesis Laboratory, Department of Cancer Biology, The Gujarat Cancer & Research Institute, Civil Hospital Campus, Ahmedabad, Gujarat, India
2 Department of Neuro Oncology, The Gujarat Cancer & Research Institute, Civil Hospital Campus, Ahmedabad, Gujarat, India
|Date of Submission||22-Nov-2018|
|Date of Decision||18-Nov-2019|
|Date of Acceptance||13-May-2020|
|Date of Web Publication||06-Nov-2020|
Dr. Trupti I Trivedi
Clinical Carcinogenesis Laboratory, Department of Cancer Biology, The Gujarat Cancer & Research Institute, New Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Medulloblastoma (MB) is a devastating illness with unmet therapeutic needs, predominantly cytotoxic and nontargeted approaches. Survivors of MB also suffer from severe treatment-related effects of radiation and cytotoxic chemotherapy keeping mortality rate significant. Recently, four distinct molecular subgroups of MB have been identified (WNT [wingless], SHH [sonic hedgehog], Group 3, and Group 4). Novel subgroup-specific therapies are being explored in the daily treatment of patients as a clinical trial and are an important challenge in the near term for the pediatric neurooncology society. Epigenetic modifiers are also recurrently affected in MB suggesting that epigenetic therapy can be considered in a subset of patients. Moreover, a hint on forefront procedure; tracer of cancer’s genetic information entitled “liquid biopsy” in MB is described. This review examines the recent scientific progress in MB research, with a focus on the genes, pathways that drive tumorigenesis and the advances in conventional and targeted therapy. The identification of subgroup-specific, actionable therapeutic targets has the potential to revolutionize therapy for patients with MB and results in significantly enriched overall survival.
Keywords: Genetic syndromes, liquid biopsy, medulloblastoma, molecular pathways
|How to cite this article:|
Rawal ZD, Upadhyay VA, Patel DD, Trivedi TI. Medulloblastoma under siege: Genetic and molecular dissection concerning recent advances in therapeutic strategies. J Pediatr Neurosci 2020;15:175-82
| Introduction|| |
In 1925, Bailey and Cushing introduced the term “medulloblastoma (MB)” projecting a series of tumors found in the cerebellum or medulla/brain stem of mostly children. According to the Central Brain Tumor Registry of the United States (CBTRUS) (January 2018), MB accounts for approximately 20% of all childhood brain tumors (CBTs) and 64.3% of all embryonic tumors in pediatric patients (0–19 years). The rate of Indian children diagnosed every year with brain tumor has increased drastically by 15% and MB with an incidence of over 2500 Indian children per year.
MB is classically considered as a round blue cell tumor of the cerebellum that occurs exclusively in the posterior fossa and has the potential for leptomeningeal carcinomatosis. A recent study showed a link between an elevated risk of MB and genetic and environmental factors. For instance, genetic disorders such as Gorlin syndrome, Turcot syndrome (TS), and Li–Fraumeni syndrome (LFS) are cancer predisposition syndromes. Environmental factors including even parental exposures to various solvents and chemicals like benzene, chlorinated and polycyclic hydrocarbons (PAHs), whenever during the 5-year time frames prior to conception.
The key symptom of MB includes nausea and vomiting with obvious reason for stimulation of the vomiting center, an area known as the chemoreceptor trigger zone (CTZ) (also called as area postrema), in the fourth ventricle of the brain. Also, a combination of signs and symptoms of cerebellar dysfunction and increased intracranial pressure (ICP) are frequently encountered in MB. Classic symptoms of increased ICP include irritability, lethargy, nausea and vomiting, morning headaches, anorexia, and behavioral changes. Signs of cerebellar involvement may differ depending on the location of the lesion. Also, severe symptoms caused due to cerebellar dysfunction include trouble walking, ataxia, and poor coordination. In many cases, the tumor can spread to the spinal cord known as drop metastases, causing another set of symptoms, such as back pain.
Multimodality therapy for MB includes surgical resection and conventional irradiation using proton beam instead of electrons or photons. In addition, reduced-dose craniospinal irradiation is usually combined with concurrent single drug (vincristine) and followed by a multi-chemotherapeutic regimen that can be cisplatin, vincristine, and lomustine, or cisplatin, vincristine, and cyclophosphamide. For recurrent MB, stem cell transplant, mainly autotransplantation, may be used. Nevertheless, inconveniency in treatment planning due to lack of directional therapy leads to more than 60% of children treated as part of a clinical trial with the aim of improving prognosis and reducing treatment sequelae.
However, these course of therapies have increased 5-year overall survival rates over 70%–80% for standard-risk patients with MB, 60%–65% for high-risk patients, and 30%–50% for infants with localized disease. Metastatic MB shows dismal results with 5-year survival rate over 30%–50%. Recent research showed 5-year progression-free survival (PFS) of approximately 80% using systemic chemotherapy regimen with intraventricular methotrexate, thus indicating that a tailored use of drugs can replace radiotherapy for certain subgroups of patients (e.g., desmoplastic/nodular variants pathologic subgroup of MB is predictive of a superior survival rate).,
| Molecular Mechanisms for Targeted Treatment Strategies and Current Clinical Status|| |
Molecular biological studies have created a new understanding of MB, revealing key cell signaling pathways that promote tumor growth. These studies have identified molecular markers, and an analysis of the genomic aberrations in each subgroup reveals several potential actionable targets, including some targets that are already under investigation in clinical trial or preclinical trials.
According to the current international consensus, MB comprises four core disease subgroups––wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4––that are histologically similar but clinically and molecularly distinct entities. The core disease subgroups are named after cell pathways WNT and SHH, in which the respective mutations occur, whereas Groups 3 and 4 differ by the aggressiveness of the disease and age of occurrence. These molecular disease subgroups revealed distinct genomic events, several of which offer the potential for actionable targets for therapy intended for improved clinical management.
Biologically, the WNT subgroup of MB is characterized by mutations in the WNT signaling cascade, and subsequent aberrant activation of the canonical WNT signaling pathway [Figure 1]A. Germline mutations of the WNT pathway inhibitor Adenomatous Polyposis Coli predispose patients to TS, which includes a susceptibility to several cancers including MB.
|Figure 1: Subgroup specific actionable molecular pathway in MB. (A) Activated canonical wingless (WNT) signaling in the WNT subgroup. Recurrently, mutated signaling intermediates are highlighted with cross symbol. (B) Integrated genomics approaches delineate recurrent alterations affecting sonic hedgehog (SHH) subgroup. (C) Recurrent SCNA suggests TGF-β signaling as a potential therapeutic target Group 3 MB. Recurrently, mutated signaling intermediates are highlighted with cross symbol. Solid and dashed arrows indicate positive and negative signaling effects, respectively|
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The somatic mutations found in the WNT subgroup are the CTNNB1 gene (encoding β-catenin, tumors that show monosomy 6) (90%), DDX3X mutations (exploited as a therapeutic target in early in vitro studies), and TP53 mutations (12%) [Table 1]., A potential choice for targeted therapy is WNT inhibitors, of which several are currently in early Phase I/II clinical trials for WNT-activated solid tumors in adults.
Truly, a preclinical murine model of WNT MB with lesions in CTNNB1 and TP53 has been engendered that faithfully recapitulate human WNT MB, and will likely serve as a very useful preclinical model for any novel therapeutics in this subgroup. However, patients with WNT subgroup MB have excellent survival rates of 95% with conventional therapy, and as such current interest is focused on de-escalation of therapy in this group of patients.,
Sonic hedgehog subgroup
Somatic mutations in SHH pathway genes such as PTCH1, SMO, and SUFU are present in addition to amplifications of GLI1, GLI2, and MYCN [Figure 1B]. The SHH subgroup is currently the best-studied subgroup of MB. SHH pathway receptors such as Patched 1 (PTCH1), suppressor of fused (SUFU) or smoothened (SMO) are collectively found in 10%- 15% of sporadic MB that lead to expression of the oncogenic transcription factor GLI1.,
A panel of these alterations has been successfully used to develop murine SHH MB models, which faithfully recapitulate human disease. These in vitro and in vivo studies suggested that SHH pathway inhibitors (especially SMO-GDC-0449 and LDE225) constitute promising therapeutic agents for this MB subgroup., Indeed, several mechanisms of SMO inhibitor resistance have been reported including mutations in SMO allowing resumed SHH signaling, amplification of the downstream effector GLI2, or upregulation of the PI3K pathway. Efforts have been made to develop targeted therapies inhibiting the SHH pathway.
One therapeutic approach is SMO inhibition with vismodegib. However, only SHH MBs with mutations in PTCH1 or SMO can benefit from this molecule. A more recent therapeutic approach refers to epigenetic treatments with bromodomain (BET) inhibitors. BET inhibitors have been shown in vitro and in vivo to decrease cell viability and proliferation in SHH MB, but no clinical trial has yet examined BET inhibitors as potential therapeutics for this MB group of patients. Considering metastatic SHH MB, the MET inhibitor foretinib has been shown to decrease tumor cell proliferation and induce apoptosis in vitro and in vivo, which confers a strong rationale for its clinical evaluation. Moreover, for this subgroup of patients, a clinical trial is ongoing on to evaluate doublet therapy comprising the cyclin-dependent kinase (CDK)4/6 inhibitor ribociclib with either gemcitabine, trametinib, or sonidegib in adults with refractory or recurrent SHH MB. Alternative SHH inhibitors may constitute itraconazole or arsenic trioxide, which lead to increased degradation of the GLI transcription factor. Both agents may be particularly suitable in tumors that developed resistance to SMO antagonists, as secondary resistance was mainly caused by GLI2 amplifications in preclinical models.,
In addition, phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKt)/mammalian target of rapamycin (mTOR) or protein kinase A (PKA) signaling inhibitors are of potential interest for signaling cascades that are targeted by mutations and result in GLI activation., Drugs targeting the TP53 pathway such as Nutlin-1 allow the remaining wild-type copy of TP53 to be active, thus negating the deleterious effects of dominant negative TP53 mutations (13% of SHH tumors). Current efforts are however focused on proper patient selection in trial design of upfront therapy with SMO inhibitors.
Group 3 MB patients have the worst clinical outcome, with 5-year survivals of approximately 50% along with high rate of metastatic dissemination at diagnosis. Low proportion of recurrent Single Nucleotide Variants makes this group remarkable and can be considered as a copy number-driven subgroup. This subgroup is characterized by Myelocytomatosis amplification resulting in high MYC mRNA expression levels compared with Group 4 and SHH tumors.
In addition, transcriptional profiling revealed a retinal gene signature in G3 tumors. Due to the poor outcome of patients with G3 tumors, there is an imperative need for novel therapies, specifically in those patients harboring high-level MYC amplifications. Indeed, MYC amplification is the most common somatic copy number alteration (SCNA) identified in this subgroup, and is commonly associated with a fusion of the noncoding exon 1 of PVT1 and exon 2 of MYC. Per se, inhibition of MYC is an interesting, yet challenging, therapeutic strategy for this subgroup. Several small molecular inhibitors of MYC have been proposed and also some are in early clinical trials. Added possible strategy to target MYC might be to inhibit downstream effectors of MYC, specifically, the BET bromodomain proteins, and indeed this strategy has proven to be successful in several preclinical models of various MYC-driven malignancies. The transforming growth factor beta (TGF-β) signaling pathway is also upregulated in approximately 20% of cases as evidenced by somatic copy number aberrations, and currently there are several trials of TGF-β inhibition for a multitude of cancers [Figure 1C]. Isochromosome 17q constitutes the most frequent broad genomic imbalance. Actionable targets driven by this alteration remain to be identified. A murine allograft model of Group 3 MB exists that is driven by the overexpression of MYC and inactivation of TP53 in the CD133 neural stem cells of the postnatal cerebellum, which can be used in future preclinical trials.,
The most prevalent Group 4 subgroup with a high male and female ratio has a propensity for metastatic dissemination at diagnosis and an intermediate prognosis with a 5-year overall survival rate of approximately 75%. The cell of origin is unknown for this subgroup, and currently a possible preclinical model of Group 4 MB exists with MYCN overexpression under the GLT1 promoter. Genomically, they are characterized by a high incidence of isochromosome 17q, recurrent tandem duplications of the Parkinson’s related gene SNCAIP and MYCN amplifications. SNVs in histone modifiers are also enriched in this subgroup; specifically, mutations in the H3K27me3 demethylase KDM6A occur in 13% of Group 4 and mutations in the H3 methyltransferase MLL3 in 5%. As such, epigenetic modifying drugs may be an attractive therapeutic strategy in a subset of Group 4 patients. Deletions affecting NFKBIA and USP4, regulators of the nuclear factor kappa B (NF-kB) pathway, are enriched in Group 4 patients making NF-kB a possible rational therapeutic target. As with inhibition of downstream effectors of MYC in Group 3, inhibition of downstream effectors of MYCN is possible therapeutic targets, and recently it has been shown that BET inhibition in MYCN-driven neuroblastoma is effective in preclinical models. Identification of subsets of Group 4 with a poor prognosis may also help with personalizing therapy, whereby escalation of current therapies can be considered in high-risk cases. Conversely, delineation of patients with good prognosis in spite of metastatic dissemination would be ideal candidates for therapy de-escalation, specifically, as these patients currently receive high doses of craniospinal irradiation.
Mutations can comprehend in genetic predisposition to the development of MB through defects in pathways important in the pathogenesis. Therefore, it is fundamental to understand pathogenesis underlining MB.
| Medulloblastoma Ontogenesis: Propounding Pathogenicity|| |
Although MB is thought to originate from embryonal cells at an early stage of development, the origin of cells depends on the MB subgroups. For instance, WNT tumors originate from the lower rhombic lip of the brainstem and SHH tumors originate from the external granular layer., According to the World Health Organization (WHO) classification, pathologically MB is distinguished in three main variants: classic, desmoplastic, and large cell (LC)/anaplastic MB.
Classic tumor has a high ratio of nuclear:cytoplasm and is densely cellular with sheets of hyperchromatic round/oval nuclei. Classical type of MB is capable of neuronal differentiation. The neuronal phenotype is characterized by ostensible name Homer–Wright rosettes which are formed by cells surrounding fibrillary matrix.
Desmoplastic variants, arising in the internodular regions, contain important reticulin-free nodules of tumor cells with a lower density than the tissue in internodular zone. Cells in nodules have a lower nuclear:cytoplasm ratio compared to surrounding cells. Recent reports suggest that clinicopathologic classification of MB correlates with the expression of OTX1 and OTX2 transcription factors. It has been found that practically all MBs express OTX1 and/or OTX2. The study evidently showed that the expression of OTX1 mRNA was solitary correlated with the desmoplastic subtype.
LC tumor is composed of LCs amid round nuclei and abundant cytoplasm compared to classic MB. LC MBs are composed of larger neoplastic cells with nuclear pleomorphism and a high mitotic activity. Recently, anaplastic term has been associated with the LC MBs for high mitotic activity and an abundant apoptosis. Anaplastic MB overlaps with the large variant and are more aggressive forms than the classic type. LC/anaplastic MBs with myogenic, melanotic, and neuronal differentiation are rare tumor.
In general, therapeutic molecular markers that are widely used are CTNNB1, PTCH1 and GLI1, and MYC for classic, desmoplastic, and LC MB tumors, respectively. Novel therapeutic molecules that are underdevelopment for classic tumors are SMARCA4, DDX3X, ALK, CDK6, SNCAIP, and KDM6A. Rare molecules that are studied for desmoplastic tumors include MYCN, SMO, SUFU, TERT, and IDH1. However, OTX2, MYC, SMARCA4, and GFI1 are some of the molecules being recently studied for therapeutic purpose in LC MB tumors.
| Hereditary Maladies|| |
Although MB is usually sporadic, there are a number of uncommon predisposing germline mutation syndromes, including Gorlin syndrome, TS, and LFS. Recent research also showed the molecular implications of finding MB in a child with Rubenstein–Tyabi syndrome. Genetic syndromes associated with MB are distinctly rare (<7% of cases) but the specific mutations and aberrant signaling pathways that lead to the phenotypic features of these syndromes have in turn provided cues to the possible origins of this aggressive tumor.
The autosomal dominant genetic disorder is characterized by intracranial ectopic calcifications, skeletal abnormalities, intellectual disability, odontogenic keratocysts, hyperkeratosis of the palms and soles, facial dysmorphism and a predilection for tumor formation, including MB, multiple basal cell carcinomas and ovarian fibromas. Gorlin syndrome is caused by a germline mutation in the PTCH1 gene that is present on chromosome 9q22.32. MB that occurs in Gorlin syndrome (2%–5% cases) is typically of the nodular/desmoplastic type, hemispheric in location, and arises as a direct consequence of the PTCH mutation and activation of the SHH pathway in all cases. SHH pathway aberrations (PTCH1, SUFU, and SMO) are found in approximately 15% of patients with MB.
It is characterized by the development of primary brain tumors of the central nervous system (CNS) such as MB and glioblastoma multiforme (GBM) accompanied by numerous adenomatous colorectal polyps and colonic adenocarcinoma. It can genetically have distinguished as either hereditary nonpolyposis colon carcinoma (HNPCC) or familial adenomatous polyposis (FAP) inherited in an autosomal dominant fashion., TS can be divided into two types: TS Type I comprising classic CNS tumor associated with HNPCC, presence of glial tumors, moderately few colonic polyps, and cancer and TS type II comprising tumor most associated with FAP, presence of thousands of colonic polyps, and an elevated risk of MB.
It is a cancer predisposition syndrome, an autosomal dominant disorder associated with the development of the classic tumors, including soft-tissue sarcoma, brain tumors, osteosarcoma, premenopausal breast cancer, adrenocortical carcinoma (ACC), and leukemias. Approximately 70% of patients harbor heterozygous germline mutations of TP53, the gene encoding the p53 tumor suppressor. However, MB hardly occurs in p53−/− mice; homozygous loss of p53 accelerates the rate and frequency of occurrence of this tumor in PTCH+/− or MYC expressing mouse models. For instance, mutant p53 enriched with SHH MB and amplifications of their genes (such as MYCN, IGFRI, and GLI2) were found in the tumor, accounting for deregulation of the pathway, tumor formation, and significantly worsening prognosis. The germline p53 mutation can prime cells for tumor development due to excessive toxicity from deoxyribonucleic acid (DNA)-damaging agents (chemotherapy and radiotherapy), aberrant cell cycle control senescence or apoptosis, and a failure to induce cell cycle arrest.,
| Epigenetic Permutation Related with Medulloblastoma|| |
Numerous epigenetic alterations exist across all MB subgroups, specifically in Groups 3 and 4. Epigenetic alterations are of immense interest as several approved drugs target these epigenetic changes, specifically, the histone deacetylase inhibitors such as vorinostat, romidepsin, and valproic acid, for several brain tumors. Epigenetics is the heritable changes that do not involve perturbations in nucleotide sequences. These modifications are mediated by DNA methylation, histone modifications, chromatin remodeling, microRNAs, and long noncoding RNAs (LnRNAs).
DNA methylation is one of the well-characterized epigenetic phenomena, which typically ensues at CpG islands in the promoter region of genes resulting in transcriptional repression. However, it is unclear at the present time how targeting DNA methylation as a therapeutic strategy pertains to MB. Histone modifications including ubiquitylation, acetylation, phosphorylation, and sumoylation are modified by epigenetic modulators. Noncoding RNA (ncRNA) including microRNAs (miRNAs) and LnRNAs regulates gene expression (typically gene silencing) at the transcriptional or posttranscriptional level.
Epigenetic changes occur spatially and temporally throughout development and influence processes such as DNA repair, cell cycle, and cellular differentiation. Epigenetic regulation plays an important role in cancer, often resulting in the silencing of tumor suppressor genes or activation of oncogenes. Therefore, the role of epigenetic modifications in disease pathogenesis could be an emerging focus for cancer therapeutics.
| Dissemination and Growth of Circulating Tumor Cells in MB Leptomeningeal Metastases|| |
Although the preponderance of morbidity and mortality increases in patients with MB due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Most MB metastases are exclusively located on the leptomeningeal surface of the brain and spinal cord that contains cerebrospinal fluid (CSF); therefore, dissemination is thought to occur through shedding of primary tumor cells into CSF followed by distal reimplantation on the leptomeninges. Garzia et al. evidently showed that MB circulating tumor cells (CTCs) can also spread through the blood to the leptomeningeal space to form leptomeningeal metastases.
The mechanism including gene expression profiling revealed that the chemokine CCL2 (chromosome 17q) was overexpressed in human metastic MB compared to control primary MB. Concurrently, the coexpression of CCL2 and its receptor CCR2 enhanced the metastic potential of MB cells. Conversely, knockdown of genetic CCL2 evidently reduced the metastatic potential of the standard MB cell line (Med411H); likewise, CCR2–/– mice implanted with D425S cells. Subsequently, suggesting a hematogenous route for MB dissemination show that CTCs, one of the most investigated analytes of liquid biopsies, contribute to leptomeningeal spread.
Consequently, this liquid biopsy can advance the diagnosis and monitoring of the diseases (also relapse state post-treatment) by treating lethal disseminated MB with an advantage of being non-invasive. Moreover, for MB patients, liquid biopsy can be used widely to track tumors and mutations over duration of time. There is a significant potential for liquid biopsy that can revolutionize cancer diagnoses and treatments with the goal of turning a blood test for brain tumors into a reality for our patients.
| Conclusion|| |
For modest improvements in outcome and efficacy equivalency studies, sufficient numbers of patients are required to achieve statistically relevant endpoints. There has been a tremendous paradigm shift in our understanding of the pathogenesis and biology of MB. The advent of rational treatment strategies has been relatively delayed in MB compared to other cancers such as breast and leukemia. However, the recent identification of numerous novel therapeutic targets holds promise for targeted and less toxic therapies. Treatment strategies based on biology and not simply on clinical risk stratifications are starting to emerge especially in patients with tumors belonging to WNT and SHH subgroups. There is an urgent clinical need to shift research focus toward the less well-understood subtypes such as MYC-amplified tumors to understand the driver mutations. Key information is provided by the wealth of genome-based data available and novel preclinical patient-derived tumor models. Recent advances and developments in drug discovery and immunotherapy often offer hope to improve cure rates for patients with MB while allowing these children to reach adulthood with an increased health span.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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