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Table of Contents
REVIEW
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 92-99

Molecular and clinical correlates of medulloblastoma subgroups: A narrative review


1 Division of Hematology/Oncology, Hospital for Sick Children; Programme in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, Toronto, ON, Canada
2 Division of Hematology/Oncology, Hospital for Sick Children; Programme in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children; Departments of Medical Biophysics and Pediatrics, University of Toronto, Toronto, ON, Canada

Date of Submission02-Nov-2021
Date of Decision20-Nov-2021
Date of Acceptance01-Dec-2021
Date of Web Publication13-Jan-2022

Correspondence Address:
Dr. Vijay Ramaswamy
686 Bay St., 17-9705 PGCRL, Hospital for Sick Children, Toronto, ON
Canada
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_18_21

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  Abstract 


Medulloblastoma is a major cause of cancer-related morbidity and mortality in children, as a significant proportion of patients succumb to their disease and most survivors are left with life-long sequelae of therapy. Prior medulloblastoma classification systems relied heavily on histology and failed to account for tumor biology. The upcoming 2021 WHO classification of central nervous system tumors now firmly establishes that medulloblastoma actually comprises at least four distinct molecular entities, with considerable substructure within each group. For the first time, the study design of contemporary clinical trials has now recognized the molecular heterogeneity of medulloblastoma. The incorporation of routine molecular subgrouping into upcoming clinical trials has the potential to significantly improve survival and quality of life for children and adults diagnosed with medulloblastoma. This review was conducted to summarize these recent advances in the genomics of medulloblastoma and to summarize the timely results of molecularly-informed published clinical trials. Specifically, English language literature will be reviewed in addition to the results of SJMB03, ACNS0331, and ACNS0332.

Keywords: Genomics, medulloblastoma, sonic hedgehog, subgroup, wingless


How to cite this article:
Coltin H, Ramaswamy V. Molecular and clinical correlates of medulloblastoma subgroups: A narrative review. Glioma 2021;4:92-9

How to cite this URL:
Coltin H, Ramaswamy V. Molecular and clinical correlates of medulloblastoma subgroups: A narrative review. Glioma [serial online] 2021 [cited 2022 Jun 27];4:92-9. Available from: http://www.jglioma.com/text.asp?2021/4/4/92/335759




  Introduction Top


Medulloblastoma is a malignant embryonal tumor of the cerebellum originally described by Cushing and Bailey in 1925.[1] It is common among children and becomes less prevalent with increasing age; the incidence is 0.48/100,000 in the 0–14-year age group and 0.11 and 0.02/100,000 in the 15–39-year-old and over 40-year-old populations, respectively.[2] Historically, ascertaining the incidence of medulloblastoma was difficult as these tumors could not be histologically distinguished from other undifferentiated tumors in the cerebellum, such as atypical teratoid/rhabdoid tumors or embryonal tumors with multilayered rosettes.[3] The integration of molecular profiling techniques has allowed medulloblastoma to be recognized as a distinct entity from other embryonal tumors in the posterior fossa.[4],[5] It is now established that medulloblastoma comprises four disease entities, each with its own distinct transcriptional profile, genetic events, and clinical characteristics: wingless (WNT)-activated, sonic hedgehog (SHH)-activated, Group 3, and Group 4.[6],[7] Even within these subgroups, there is significant heterogeneity, with four molecular subtypes of SHH and 8 subtypes among Group 3 and Group 4 having been identified.[8],[9],[10] The identification of these subgroups and subtypes has important risk stratification and prognostic significance and now informs treatment approaches as evidenced by contemporary clinical trials.

Before the recognition of biological heterogeneity within medulloblastoma, no treatment stratification approaches existed. Patients were treated surgically until the 1950s when craniospinal irradiation (CSI) with posterior fossa boost was introduced; this treatment modality led to improved clinical outcomes at the cost of devastating neurocognitive sequelae among younger patients.[11],[12],[13] The prevalence of these serious late effects prompted a series of trials focused on delayed radiation for young children or radiation avoidance.[14],[15] Currently, infants with medulloblastoma, defined as children <5 years of age, are treated with radiation-sparing approaches, while those older than 5 years of age are classified as having average-or high-risk disease and are treated with risk-adapted CSI and cisplatin-based chemotherapy.[12],[16],[17] Average-risk disease confers a 5-year event-free survival (EFS) of approximately 80%–85%, in contrast to <70% for high-risk disease.[18],[19],[20],[21],[22],[23],[24],[25],[26],[27] Adults with medulloblastoma remain a neglected population, and treatment is controversial.[28] The majority are treated with CSI alone, though adjuvant chemotherapy using the Packer regimen[29] is becoming more common and may improve survival outcomes.[30],[31]

Importantly, contemporary risk-stratification approaches which reflect the 2021 WHO classification system incorporate not only clinical variables such as patient age, metastatic status, and residual tumor volume but also disease subgroup and cytogenetic characteristics.[16],[20],[32] The clinical implications of these subgroups have recently been validated in prospective cooperative group trials by assigning subgroups post hoc to nonmolecularly informed trials, which has led to the identification of subgroup-specific treatment strategies, particularly for high-risk Group 3 patients. The purpose of this review is two-fold. First, we will review the molecular and clinical correlates that are fundamental to our current approaches to treating medulloblastoma. Secondy, we will review and summarize for the first time the findings of three recently published international clinical trials of average-and high-risk medulloblastoma (SJMB03, ACNS 0331, ACNS 0332).[19],[20],[27]


  Search Strategy Top


A search of the English language literature was conducted using the PubMed database between September 1, 2021 and October 1, 2021, using “medulloblastoma,” “pediatric,” “childhood,” “adult,” “treatment,” “risk,” “clinical trial,” “outcome,” “prognosis,” “relapse,” “molecular,” “subgroup,” “WNT,” “SHH,” “Group 3,” “Group 4” as the keywords. Articles were filtered based on relevance in the title and abstract and synthesized into the text where appropriate. The relevance of articles was based on the clinical expertise and knowledge of the authors.


  Molecular-Clinical Correlates Top


Medulloblastoma risk stratification has significantly evolved over recent years. Historically, tumor histology and clinical variables were the driving factors behind medulloblastoma risk stratification. The correlation of histology with patient outcomes has largely been replaced by molecular characterization of tumors. For example, the finding of desmoplastic histology being associated with excellent clinical outcomes highlights a subset of SHH tumors in infants, although it is now recognized that infants with SHH tumors as a whole represent a group with favorable prognosis even with classic histology.[7],[33],[34],[35] Moreover, the intraobserver reliability of desmoplastic histology in the most recent Children's Oncology Group study (ACNS1221) was low across three expert pediatric neuropathologists, calling into question the utility of the histologically based classification.[34] The limitations of tumor histology were also highlighted by the SJYC07 trial, a multicenter phase II trial of young children with medulloblastoma who received induction chemotherapy, risk-adapted consolidation therapy, and oral maintenance therapy.[36] A post hoc review of SJYC07 also suggests that the association between desmoplasia and SHH activation increases over time, suggesting that pathological interpretation is evolving as molecular correlates are increasingly identified.[36] A similar overlap exists between large-cell/anaplastic tumors on histology with SHH-TP53–mutant tumors or Group 3 tumors with high-risk features such as MYC amplification.[4],[12],[33],[37],[38] Anaplastic histology remains an exclusion criterion for many average-risk trials as a result of the historical association with poor outcomes.[18],[19] Despite such associations between histological features and medulloblastoma subgroups, contemporary clinical trials have shifted toward molecular classification as their foundation as a way to mitigate the limitations of histologically-based prognostication.[16]


  Contemporary Clinical Trials Top


The recent publication of the results of three molecularly-informed international clinical trials has prompted this review and the study details will be reviewed here. The first trial, SJMB03, was a risk-adapted Phase III trial of 330 average-and high-risk patients aged 3 years and older.[20] Enrollment risk stratification was based on metastatic status and extent of resection. By correlating the biological features of tumors within subgroups and subtypes with outcomes, the investigators were able to create new molecularly-based risk stratification approaches for SHH as well as Group 3 and Group 4 tumors.[20] The Children's Oncology Group study, ACNS0331, randomized children with average-risk medulloblastoma to receive either posterior fossa radiation therapy or involved field radiation therapy after CSI.[19] Younger children underwent a second randomization between standard-dose and low-dose CSI.[19] Involved field radiation therapy was found to be noninferior to posterior fossa radiation therapy but low-dose CSI resulted in worse outcomes compared to those who received standard-dose CSI.[19] Subgroup-specific analyses were conducted post hoc. The last study to be evaluated was ACNS0332, a Phase III trial of 260 high-risk patients (metastatic disease, residual disease, or diffuse anaplasia) which aimed to determine whether daily carboplatin administered during radiation therapy resulted in improved event-free survival; subgroup-specific analyses were conducted.[27] For the first time, international clinical trials were conducted according to molecular subgroups, providing a tangible application of biological advances to clinical care.

In the following sections, molecular and clinical correlates of each of the subgroups will be reviewed including novel findings from the above clinical trials and summarized in [Figure 1].
Figure 1: Clinical and molecular correlates of medulloblastoma subgroups and subtypes: A summary of clinical, genomic and prognostic features of medulloblastoma subgroups and subtypes. amp: Amplification, chemo: Chemotherapy, CNV: Copy number variation, PFS: Progression-free survival, SHH: Sonic hedgehog, WNT: Wingless

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  Wnt Top


WNT tumors carry favorable outcomes for pediatric patients and are deemed appropriate candidates for the consideration of therapy de-escalation. WNT tumors are characterized by transcriptional activation of the WNT pathway, with approximately 90% having somatic CTNNB1 mutations.[10] Of those lacking CTNNB1 mutations, pathogenic APC germline variants are prevalent and highlight the necessity of performing germline testing for Turcot syndrome for this population.[10],[39],[40] Mutations in TP53 are seen in 10%–15% of cases but are not associated with the same prognostic implications, unlike the case for SHH tumors.[35],[41],[42] Other genes that are commonly mutated in WNT medulloblastoma include DDX3X, CSNK2B, EPHA7, and subunits of the SWI/SNF nucleosome-remodeling complex (SMARCA4, ARID1A, ARID2).[10],[20] Approximately 80% of WNT tumors have monosomy 6, which is the most common recurrent somatic copy number aberration.[10] With the application of integrated clustering, two subtypes of WNT have been identified: The WNT α subtype, comprising pediatric-aged patients with monosomy 6, and the WNT β subtype, comprising older patients with only a 40% prevalence of monosomy 6.[9] WNT tumors arise from the lower rhombic lip of the brainstem and have a unique radiological pattern that frequently arises from the lateral recesses.[43],[44],[45] Preclinical data have suggested that the blood-brain barrier is compromised in WNT patients thereby facilitating the entry of chemotherapy agents, and potentially influencing their favorable outcome.[46]

WNT tumors rarely occur in patients <5 years of age,[35] and the outcomes of pediatric patients <16 years of age are excellent; the role of therapy de-escalation, specifically CSI doses of 15–18 Gy, is actively being investigated in open clinical trials (NCT: NCT01878617, NCT: NCT02724579, NCT: NCT02066220).[12],[16],[17],[19],[20],[27],[41] The excellent prognosis conferred to younger patients with WNT tumors has not been extended to older adolescents and adults; whether this finding is related to lower rates of chemotherapy use for older populations is undetermined.[47],[48],[49] Among patients with average-risk WNT tumors, EFS was not impacted by a smaller tumor boost volume or a lower CSI dose in the ACNS0331 trial.[19] The receipt of high-dose cyclophosphamide chemotherapy after radiotherapy may be associated with improved survival compared to regimens with no or intermediate doses of cyclophosphamide and/or CCNU based maintenance.[41] Relapses can occur metastatically or in the surgical cavity,[16],[50] although a unique pattern of relapses occurring in the lateral ventricles was reported in one recent study by our group.[41] Clinical variables such as metastatic disease and extent of resection have not been shown to predict relapse in WNT medulloblastoma.[26],[41],[51],[52] In three molecularly informed studies of high-risk medulloblastoma, specifically the SJMB03 and ACNS0332 trials and the HIT-GPOH high-risk study, the high-risk features of WNT tumors, such as residual disease >1.5 cm2 and metastatic disease, were not associated with a poor prognosis, suggesting that this infrequent but important group may be candidates for therapy de-escalation.[20],[26],[27] WNT tumors, even in the setting of high-risk features, are associated with favorable prognoses among pediatric patients. Future studies are required to determine the etiology of the worse outcome of adult patients with WNT tumors, including if treatment differences from the omission of chemotherapy account for the relatively poorer prognosis of adult patients with WNT medulloblastoma.


  Shh Top


SHH tumors are characterized by activation of the SHH signaling pathway through mutations or copy number aberrations.[35] SHH tumors arise from the external granule layer, as evidenced by their near-ubiquitous cerebellar location, usually in the cerebellar hemispheres.[43],[45],[53],[54] Such alterations include loss-of-function mutations or deletions in Patched (PTCH) and in Suppressor of Fused (SUFU) and activating mutations in Smoothened (SMO).[8],[10],[35],[55],[56] SMO inhibitors are being investigated as maintenance therapy in the SJMB12 trial but only in patients who have obtained skeletal maturity due to premature osseous fusion.[35],[56],[57],[58],[59] TERT promoter mutations are found in almost all adults but are present in only 10%–20% of pediatric tumors.[8],[10],[47],[60] Amplifications of GLI2 and MYCN often occur with somatic or germline TP53 mutations in older children, conferring a very poor prognosis.[8],[9],[19],[42] SHH-TP53 mutant tumors are considered a distinct entity in the WHO classification given their uniformly poor prognosis.[6] Classic somatic copy number alterations in SHH include losses of chromosomes 9q, 10q, and 17p, leading to loss of heterozygosity for PTCH1, SUFU, and TP53, respectively.[7],[10],[20],[55],[56],[61] Chromosome 2 gain occurs in some infants.[9],[10],[62] Poor prognostic markers include 10q loss, 14q loss, and chromothripsis.[47],[61] SHH tumors occur in all age groups but most commonly in infants <3 years of age and adults over 16 years of age, with 4 molecular subtypes having been identified: SHH-α (adolescents), SHH-β (infants with poor prognosis), SHH-γ (infants with good prognosis), and SHH-δ (adults).[8] In general, the prognosis for infants is favorable compared to that of older children with TP53 mutations (somatic or germline) and/or MYCN amplification, which is dismal.[16],[17],[42],[61],[63] Among adults with SHH tumors, the prognosis is intermediate, with 5-year progression-free survival rates of approximately 60%–70%; late relapses are common.[33],[47],[48],[64] SHH tumors are uncommonly metastatic at diagnosis (approximately 20%) with a mixed pattern of relapse, with 40%–60% of relapses being in the initial surgical cavity.[16],[17],[65]

All children with SHH tumors require evaluation for cancer predisposition syndromes since germline predisposition occurs in 14% of patients.[40] Infants require screening for germline PTCH and SUFU mutations causing Gorlin's syndrome, whereas older children should have their tumors sequenced for TP53 and subsequently undergo germline testing for Li-Fraumeni syndrome should somatic mutations be found.[16],[35],[66],[67],[68] Other considerations should include testing for mutations in BRCA1 and PALB2 in cases where homologous recombination repair deficiency is suspected.[35],[40] In the recently published ACNS0331 trial for average-risk patients, involved field radiation therapy versus posterior fossa radiation therapy was associated with improved EFS, which may in part be explained by the higher incidence of second malignant neoplasms in the posterior fossa radiation therapy group as a result of cancer predisposition.[19] The ACNS0332 and SJMB03 trials suggested an overall poor prognosis for high-risk SHH medulloblastoma, suggesting that new approaches are required for this group, especially as this group is enriched for patients with TP53 mutations. In SJMB03, high-risk SHH tumors were those with any of the following features: metastatic disease, large cell/anaplastic histology, TP53 single nucleotide variants or loss, MYCN amplification, GLI2 amplification, or chromosome 17p deletion.[20] Several approaches, including omission of alkylator therapy for germline TP53 patients and the introduction of novel agents, identified preclinically in bona fide SHH models into upfront therapy, such as CDK4/6 inhibition, MEK inhibitors, and CK2 inhibitors, are being explored.[69],[70],[71],[72]

Molecularly stratified treatment of SHH medulloblastoma varies by age. In infants, trials of de-escalation of therapy for those with desmoplastic histology were considered a failure, but applying post hoc molecular correlates suggested that SHH-γ disease has significantly better survival than SHH-β. Interestingly, in those studies with intensified therapy, such as HIT-SKK with intraventricular methotrexate, there was no difference in outcome between infants with either SHH-γ or SHH-β medulloblastoma, suggesting that SHH-β disease requires additional therapy. The Headstart-3 study, a prospective trial of intensive induction chemotherapy followed by myeloablative chemotherapy and stem cell rescue for young patients with medulloblastoma, was not subgrouped but showed 5-year event-free and overall survivals of 93% across all desmoplastic histologies.[73] These histologies are known to be highly enriched, where they are likely to be exclusively comprising SHH, suggesting that a single cycle of autologous transplant may be sufficient for this group.[73] SMO inhibitors are limited in their use due to premature osseous fusion in prepubertal children and their lack of efficacy in tumors with SHH activation downstream of SMO, which constitute the majority of failures. In adults, there is a potential role for SMO inhibitors; however, clinical trials are still ongoing.[56],[57],[58],[74],[75]

Group 3

Group 3 tumors occur in infants and young children, have a 3:1 male-to-female sex ratio and are metastatic in approximately half of cases.[12],[35],[55] Group 3 tumors have a poor prognosis, especially among metastatic cases and tumors with MYC amplification, which comprises 15%–20% of these tumors.[10],[27],[76],[77],[78],[79] OTX2 amplification, GFI1 and GFI1b activation, somatic nucleotide variants in SMARCA4, KBTBD4, and CTDNEP1 are other focal alterations that occur in Group 3 tumors.[10],[62],[80] Common broad copy number events include isochromosome 17, gains of 1q and 7, and losses of chromosomes 8, 10q, and 16q.[55],[62] Cancer predisposition is rare in Group 3 and Group 4, but consideration should be made for testing for PALB2 and BRCA2 germline mutations in those with concerning family histories and/or homologous recombination repair deficiency.[40] The precise cell of origin of Group 3 is not clear but appears to arise from early cerebellar precursor cells.[53],[54] Overall, the biology of non-MYC amplified Group 3 tumors is complex and poorly understood.[55]

Patients with metastatic disease have survival rates of approximately 40%, and survival is rare among patients with metastatic, MYC/MYCN amplified tumors.[16],[20],[26],[35],[55],[61],[79] Survivors with nonmetastatic disease and MYC amplification have been reported.[16],[35],[81] In ACNS0332, the addition of daily carboplatin to weekly vincristine during radiation therapy resulted in improved EFS for patients with Group 3 tumors exclusively, with a higher magnitude of improvement when restricted to patients with metastatic disease.[27] Infants with metastatic Group 3 tumors are rarely cured without the addition of CSI, although there appears to be a role for high-dose methotrexate during induction chemotherapy as part of intensive high-dose thiotepa consolidation chemotherapy.[36],[79],[82],[83] Infants treated with radiation-sparing approaches as well as irradiated children generally experience disseminated relapses with the leptomeningeal disease over short time frames.[45],[65],[84] Group 3 disease recurs almost exclusively with metastatic dissemination, irrespective of therapy, suggesting that additional treatment to the metastatic compartment is necessary, particularly in young children treated with a radiation-sparing approach.[65],[85] The availability of several preclinical models of MYC-amplified Group 3, including many patient-derived xenograft models, has led to many therapies proposed for this group, including conventional chemotherapies such as actinomycin-D, which have not previously been considered.[70]

Group 4

As with Group 3 tumors, the understanding of the biology of Group 4 tumors is limited.[35],[55] The cells of origin of Group 4 appear to be unipolar brush cells and are radiologically characterized by a higher propensity for focal metastasis and nonenhancing lesions.[53],[54],[84] Loss-of-function mutations in KDM6A, ZMYM3, and KMT2C are common and result in disrupted chromatin modifiers, which may influence the DNA damage response and tumorigenesis.[10],[55],[86],[87],[88],[89],[90] Isochromosome 17q occurs in over 80% of Group 4 tumors, with other common copy number alterations being 7q gain and 8p loss.[35] Amplifications of CDK6 and MYCN occur in up to 10% of cases, although unlike for SHH and Group 3 medulloblastoma, the poor prognostic significance of MYCN does not exist for Group 4 tumors.[9],[61],[91],[92]

Group 4 tumors represent the most frequent subgroup of tumors (40% of cases), occur in older children and less commonly adults, and have a male predominance.[7],[47] Approximately 30%–40% are metastatic at diagnosis and characteristically have longer prediagnostic and relapse latency phases.[9],[12],[65],[93] Furthermore characteristically, Group 4 tumors are not enhanced on diagnostic magnetic resonance imaging and are located in the fourth ventricle.[43],[45],[94],[95] Patients who receive radiation have intermediate survival outcomes, with 5-year progression-free survival rates of 80%–90% and 60%–70% for average-and high-risk patients, respectively.[19],[20] In the ACNS0331 trial, average-risk patients with Group 4 medulloblastoma who received low-dose CSI had inferior EFS to that of patients who received standard-dose CSI; this trend was not observed for those with Group 3 tumors.[19] Infants treated with radiation-sparing approaches have poor survival.[35],[84] Positive cytogenetic markers in children include whole chromosome 11 loss and chromosome 17 gain.[16],[27],[61] In adults, these markers do not appear to have any prognostic value, although chromosome 8 loss is associated with favorable survival.[47] Similar to Group 3 tumors, previously irradiated Group 4 medulloblastoma recur almost exclusively with metastatic dissemination, highlighting the importance of treatment of the metastatic compartment.[65] There is a paucity of patient-derived models of Group 4 medulloblastoma, which are limited to a subset of orthotopic xenograft models that require 4–8 months to propagate in the hindbrain of immunocompromised mice.[70] Transgenic models and in vitro cell lines currently do not exist for this group.


  Molecular Subgroups of Group 3 and Group 4 Medulloblastoma Top


A number of subtypes within Group 3 and Group 4 subgroups have been identified and reflect the heterogeneity within these tumors.[9],[10],[76] Subtype I is known for a balanced genomic structure, subtype II for striking chromosome 8 gain, subtype III for chromosome 10q loss, subtype IV for losses of chromosome 8, chromosome 10, and chromosome 11, subtype V for isochromosome 17q and chromosome 16q loss, subtypes VI and VII for the gain of chromosome 7 and loss of chromosome 8, and subtype VIII for isochromosome 17q.[9],[10],[96],[97] Based on the results of SJMB03, the authors proposed a new risk classification approach to Group 3 and Group 4 tumors consisting of low-risk (nonmetastatic subtype VII), intermediate-risk (nonmetastatic disease and not within III or VII subtypes), and high-risk (metastatic disease, subtype III, or MYC amplification) disease.[20] However, the role of these subtypes in relation to clinical trial design and treatment approaches is in its infancy.[55]

Limitations

This review is limited by the inclusion of English-language literature only, potential gaps in the literature search process, and the potential omission of relevant work.


  Conclusions Top


In this review, we have summarized the new developments in the understanding of molecular-clinical correlates within the medulloblastoma subgroups and subtypes. The incorporation of molecular correlates into the stratification of medulloblastoma has significantly improved our ability to classify patients into appropriate risk groups [Figure 1]. The identification of the four core subgroups is now considered the first step after the morphological diagnosis of medulloblastoma and is a crucial part of tailoring therapy. The recent publication of subgroup-informed international clinical trials has highlighted the feasibility and importance of incorporating tumor biology into the trial methodology. Most ongoing or upcoming clinical trials are incorporating molecular-based stratification of patients, and although specific targeted therapies have thus far been elusive, the post hoc subgrouping of closed clinical trials has shown a far more precise risk stratification than the use of clinical variables alone and has identified potential tailored therapies such as daily carboplatin for high-risk Group 3 patients. Through the routine application of biological risk stratification in future clinical trials worldwide, we have the unique opportunity to improve the quality of life for children with low-risk diseases and introduce new therapies to those patients facing treatment failure with current therapies.

Financial support and sponsorship

This work was supported by Garron Family Cancer Centre Fellowship to HC, and operating funds from the Canadian Institutes for Health Research, Brain Canada, and Canadian Cancer Society Research Institute to VR.

Conflicts of interest

There are no conflicts of interest.



 
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