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Review

Exploring the Molecular Complexity of Medulloblastoma: Implications for Diagnosis and Treatment

by
Julian S. Rechberger
1,2,
Stephanie A. Toll
3,
Wouter J. F. Vanbilloen
1,4,
David J. Daniels
1,2 and
Soumen Khatua
5,*
1
Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
2
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
3
Department of Pediatrics, Division of Hematology/Oncology, Children’s Hospital of Michigan, Detroit, MI 48201, USA
4
Department of Neurology, Elisabeth-Tweesteden Hospital, 5022 Tilburg, The Netherlands
5
Department of Pediatric Hematology/Oncology, Section of Neuro-Oncology, Mayo Clinic, Rochester, MN 55905, USA
*
Author to whom correspondence should be addressed.
Diagnostics 2023, 13(14), 2398; https://doi.org/10.3390/diagnostics13142398
Submission received: 16 June 2023 / Revised: 7 July 2023 / Accepted: 11 July 2023 / Published: 18 July 2023
(This article belongs to the Special Issue Medulloblastoma—Existing and Evolving Landscape)
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Abstract

:
Medulloblastoma is the most common malignant brain tumor in children. Over the last few decades, significant progress has been made in revealing the key molecular underpinnings of this disease, leading to the identification of distinct molecular subgroups with different clinical outcomes. In this review, we provide an update on the molecular landscape of medulloblastoma and treatment strategies. We discuss the four main molecular subgroups (WNT-activated, SHH-activated, and non-WNT/non-SHH groups 3 and 4), highlighting the key genetic alterations and signaling pathways associated with each entity. Furthermore, we explore the emerging role of epigenetic regulation in medulloblastoma and the mechanism of resistance to therapy. We also delve into the latest developments in targeted therapies and immunotherapies. Continuing collaborative efforts are needed to further unravel the complex molecular mechanisms and profile optimal treatment for this devastating disease.

1. Introduction

Medulloblastoma is a malignant pediatric brain tumor with vastly diverse clinical outcomes based on age, the presence of residual or metastatic disease, and histopathological and molecular classification. The 2016 World Health Organization (WHO) classification system incorporated molecular entities into their diagnoses, stratifying medulloblastoma into four major subgroups: WNT-activated, sonic hedgehog (SHH), and non-WNT/non-SHH groups 3 and 4. SHH was further divided according to tumor protein 53 (TP53) status, as these tumors have markedly different clinicopathological characteristics (Table 1). In 2021, this classification was further stratified, with the four major subgroups further delineated according to methylation profiling and pathway activation [1,2,3]. These subgroups not only demonstrate the profound genetic heterogeneity among this tumor type but are imperative to profile molecularly driven treatment strategies and outcomes.
These divergent clinical outcomes, along with clearly different clustering of tumors (even within the principal subgrouping) have led to the current 2021 WHO classification system [2]. Like the 2016 classification, the WNT-activated group is present, but SHH-activated tumors (TP53 wild type) are now divided among four subgroups discovered in DNA methylation or transcriptome profiling [4,5,6]. The SHH-activated TP53 mutant is considered a separate molecular entity in the WHO classification system but falls within one of the four subgroups of TP53 wild type tumors in the more granular classification systems [4,5,6]. These subgroups not only differ in their demographic findings but in their clinical features and cytogenetic findings as well. The same holds true for non-WNT/non-SHH group 3 and 4 tumors. These tumors are now divided into a spectrum of eight new subgroups, with subgroup 1 primarily representing the previous group 3 and subgroup 8 primarily representing the previous group 4 tumors [4,6]. These novel groups provide ample opportunities to tailor care in these patients, which will hopefully result in uniformly improved outcomes among this difficult-to-treat population. The clinicopathologic and molecular (Table 2) differences among these new subgroups as well as the current and historical clinical trials incorporating them are discussed below.

2. Epigenetic Machinery in Medulloblastoma

The landscape of medulloblastoma is changing, and the importance of epigenetic dysregulation is becoming all the more apparent. Epigenetics, or changes in cell function not related to DNA sequences, is known to play a critical role in cancer development and progression, but only more recently has its importance become known in pediatric brain tumors. In medulloblastoma, several epigenetic aberrations have been implicated in the pathogenesis of the disease, predominantly in the form of DNA methylation and histone modification (Figure 1) [7,8]. It has been postulated that each subgroup has different alterations that drive tumorigenesis, with epigenetic changes occurring across all subgroups. In fact, more than 30% of medulloblastoma samples contain modifications of genes that encode epigenetic regulators, and while some of these overlap, each epigenetic signature is unique, providing insight into the drivers of each disease subgroup [9].
DNA methylation has been implicated in several tumors, including medulloblastoma. The most common form of this is within the context of CpG islands, which are frequently found near the promoter region of genes. Methylation of these islands results in permanent gene silencing with the possibility of silencing multiple genes with a single change [10,11]. Typically, these silenced genes are tumor suppressor genes, which then enable the tumor to grow unopposed. This is of clinical importance, as these changes carry prognostic value, particularly in medulloblastoma [12]. These methylation profiles are so profound that they have been used to further stratify the previously designated subgroups into both molecularly and clinically distinct entities as outlined by the 2021 WHO classification system [2,6].
Several tumor suppressor genes have been shown to be inactivated through hypermethylation of CpG islands. RASSF1A is a tumor suppressor gene located on chromosome 3 that has been shown to be almost ubiquitously hypermethylated in medulloblastoma cell lines and primary tumors. This hypermethylation results in irreversible biallelic inactivation of the RASSF1A gene, contributing to tumorigenesis [13]. In a study by Lusher et al., cell lines that were hypermethylated had RASSF1A expression restored after treatment with 5-aza-2′-deoxycytidine or decitabine (DNA methyltransferase inhibitor), highlighting the clinical implications of restoring epigenetic regulation in these tumors [13]. Additional methylation-related apoptosis has also been demonstrated in other studies, including the loss of caspase-8 mRNA expression. Similarly to RASSF1A, this expression can be restored with a DNA methyltransferase inhibitor (decitabine) [14]. Another example of CpG island methylation is the hypermethylation of HIC-1 (hypermethylated in cancer-1). This gene is a potent tumor suppressor gene whose hypermethylation has been established in multiple different tumor types and has been correlated with poor overall survival in medulloblastoma [15]. ZIC2 has also been correlated with poor overall survival. This gene has multiple functions, including interaction with proteins in the SHH pathway as well as that of beta-catenin inactivation, both of clinical and diagnostic importance in medulloblastoma [16].
CpG island hypomethylation has also been revealed in medulloblastoma [7]. In the SHH subgroup, VAV1 is an oncogene that is hypomethylated, leading to an increase in expression and therefore tumorigenic potential [17]. VAV1 hypomethylation is a frequent aberration among this subgroup at upwards of 70% but is rarely shown in other molecular subgroups. Like those genes above, its overexpression is associated with poorer clinical outcomes [17]. S100A4, although not containing a promoter-associated CpG island, is epigenetically regulated through CpG sites. The hypomethylation of this gene is pro-tumorigenic, resulting in increased expression in medulloblastoma [18]. In group 3 and 4 medulloblastoma, LIN28B hypomethylation downregulates a tumor suppressor gene family, as it results in a novel promoter [19].
In addition to methylation aberrations in medulloblastoma, histone modifications are also prevalent and of clinical significance. These modifications lead to changes that impact transcription, and mechanisms include acetylation, phosphorylation, methylation, and ubiquitination. One prominent example is alterations in H3K9 (histone 3, lysine 9), which is imperative to stem cell maturation and has been implicated in several cancers, including medulloblastoma. One study by Northcott et al. found that approximately 40% of medulloblastoma samples had H3K9me3 lower than controls [20]. Single copy number aberrations (SCNAs) have also been identified that impact this specific chromatin modification, including EHMT1, SMYD4, JMJD2C, MYST3, L3MBTL3, and SCML2 [9,21].
Chromatin dysregulation is not limited to H3K9 but also includes H3K4 and H3K27 methylation. The methyltransferases involved are mutated in select medulloblastoma samples irrespective of the subgroup [9]. Within groups 3 and 4, modifiers of H3K27 methylation have been described as potentiating tumor growth and proliferation. In this study, these subgroups were defined by high levels of EZH2 expression as demonstrated by H3K27me3 and impaired H3K4 methylation [22]. This methylation has been postulated to mirror the oncogenic actions that have been shown in other cancers that accelerate tumor development and propagation [20].
Histone acetylation and deacetylation are also prevalent in medulloblastoma across subgroups, in some cases correlating with prognosis [23]. Among those mutated are genes encoding for CBP and p300 (CREBBP and EP300, respectively), which acetylate H3K27 [9]. Interestingly, this alteration is disproportionally increased in SHH medulloblastoma and present in almost 19% of the subgroup [24]. hMOF is a histone acetylase for H4K16, the downregulation of which is linked to poor overall survival [23]. These aberrations are clinically relevant, and as such, HDAC inhibitors are being evaluated within the context of clinical trials in medulloblastoma.
In addition to histone modifications and methylation, microRNA (miRNA) and mRNA are now emerging as a component of tumor pathogenesis, particularly in medulloblastoma. MicroRNAs are small non-coding RNAs that downregulate gene expression, leading to mRNA cleavage or translational and transcriptional repression [25]. Clustering analysis in medulloblastoma demonstrates that primary specimens can be classified into different subgroups according to miRNA expression [25]. Both downregulation and upregulation have been reported to act on targets within the SHH pathway, the MYCN and MYC pathways, GLI1, SMO, and CDK6, among others [26]. Interestingly, miRNA expression has not only been correlated with the subgroup but also with average-risk versus high-risk classification. In one study by Ferretti et al., lower expression of two miRNAs (miR-31 and miR-153) was found in high-risk versus average-risk tumors [27]. While both upregulation and downregulation have been demonstrated, the majority of miRNAs are downregulated; suggesting that they have antiproliferative properties that are eradicated when they are no longer functioning [27]. Together, it is clear that miRNA plays a critical role in medulloblastoma development and propagation and warrants further investigation in both pathogenesis and possible clinical targets.

3. Current Treatment Paradigms and Novel Therapies

3.1. Standard-of-Care Therapy

Therapy for medulloblastoma for all subtypes is multimodal and combines surgery, chemotherapy, and (depending on age) craniospinal irradiation or autologous stem cell rescue. Specific regimens, including chemotherapeutic agents and use of irradiation, are primarily dependent on risk stratification. Historically, definitions of average risk and high risk were driven by both metastatic disease status and extent of resection; however, reliance on these definitions alone resulted in significant differences in clinical outcomes [11]. Additionally, recent study results from the Children’s Oncology Group also demonstrated this same diversity, necessitating a change in our approach to this disease entity [28]. These results, along with the molecular heterogeneity demonstrated by genetic profiling, have led to shift toward more molecularly stratified treatment regimens [11,29].
Current treatment regimens are now designated not only by age and metastatic and resection status but by medulloblastoma subtype as well. In addition, while the 2021 subgrouping provides valuable prognostic and therapeutic implications, the most recent treatment regimens are based upon the four principal subgroups from the 2016 WHO classification system. One of the most prominent examples of this is WNT-activated medulloblastoma, which has been shown to have a favorable outcome (even when metastatic) with a 5-year event-free survival (EFS) of over 90% [30,31,32]. Given this, in conjunction with previous trials revealing non-inferior outcomes with less chemotherapy, the Children’ Oncology Group is currently studying reduced irradiation and chemotherapy for this subgroup (NCT02724579). Similarly, Leary et al. published results of a high-risk medulloblastoma study (ACNS0332) in 2021 that demonstrated improved survival exclusively in the high-risk group 3 cohort when carboplatin was used in conjunction with craniospinal irradiation [28]. This study, like that of the WNT-activated study, highlighted the diversity within this disease entity. Moving forward, the therapies will likely be further segregated via definitions of high and average risk incorporating molecular findings as well as metastasis and extent of resection.

3.2. Targeted Therapies

Although the last two decades have witnessed improvement in the survival rate of medulloblastoma, toxic adverse effects and concerns regarding long-term sequelae have undermined therapeutic efficacy [33]. A paradigm shift toward personalized targeted therapy for medulloblastoma that aims to reduce the side effects of standard cytotoxic agents without compromising therapeutic efficacy is now favored and pursued [34,35,36]. While personalized treatments for each medulloblastoma subgroup and subtype are still in their infancy, some driver mutations and inhibitors that target these mutations or interfere with aberrant signaling pathways have been discovered in WNT-activated and SHH-activated tumors and are undergoing extensive in vitro and in vivo testing [37]. Conversely, the biology of non-WNT/non-SHH group 3 and 4 tumors is not as well understood, which currently limits the application of novel targeted therapies to some general genetic and epigenetic targets [38]. The following section discusses some potential subgroup-specific targets for SHH and WNT medulloblastoma as well as broader targets in clinical development for all subgroups (Figure 2).

3.2.1. Hedgehog Signaling Pathway

SHH-activated medulloblastoma is characterized by mutations in hedgehog (HH) target genes that lead to a constitutively active signaling pathway [37,39]. Small-molecule inhibitors that target factors implicated in HH signaling are being developed as potential therapeutics. The SMO inhibitor vismodegib (GDC-0449) is FDA approved for the treatment of SHH-dependent cancers and is in clinical testing for medulloblastoma. Tumor regression and a stable response to vismodegib were observed in patients with refractory metastatic disease [40,41]. Several clinical trials evaluating the impact of vismodegib alone or in combination with adjuvant chemotherapy were subsequently initiated (e.g., NCT01878617, NCT01601184, and NCT00822458). Results from the phase II Pediatric Brain Tumor Consortium studies PBTC-025B (NCT00939484) and PBTC-032 (NCT01239316) showed targeted efficacy of vismodegib against recurrent SHH-activated medulloblastoma, with SMO inhibitory action varying according to the genomic aberrations present in the tumor [42]. Vismodegib resistance can result from SMO mutations as well as mutations in HH genes upstream or downstream from SMO. Furthermore, it was reported that high-risk patients harboring SUFU mutations or MYCN/GLI2 amplifications did not respond to SMO inhibition but still developed growth-plate fusions because of drug exposure [43,44,45]. Sonidegib is another SMO antagonist that has been examined clinically in medulloblastoma (NCT01125800, NCT01708174). A phase I clinical trial of oral sonidegib in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma established well-tolerable dose levels and found complete or partial responses in half of the medulloblastoma patients with activated HH signaling [46]. Preliminary reports of sonidegib in the adjuvant setting in high-risk patients or heavily pretreated patients with leptomeningeal disease further support the potential clinical benefits of this drug [47].
A viable alternative to SMO inhibition is to directly or epigenetically target the transcription factor GLI, which is a terminal effector of HH signaling that is involved in initiating the transcription of HH target genes [48,49]. Silmitasertib (CX-4945) is a potent and selective casein kinase 2 inhibitor with the ability to block GLI. This drug is presently in phase I/II clinical testing (NCT03904862) for patients with recurrent or CDK4/6 pathway relapsed SHH-activated medulloblastoma [50].

3.2.2. PI3K/AKT/mTOR Pathway

Alterations of the PI3K/AKT/mTOR signaling pathway are known to play a crucial role in medulloblastoma [51,52]. Extensive preclinical research has demonstrated that drugs targeting PI3K and its downstream signaling possess radiosensitizing effects and are beneficial alone or in conjunction with adjuvant cytotoxic chemotherapy [51,53,54]. Even more anti-tumor effects were observed in vitro and in vivo with the combination of PI3K (BYL719) and mTOR (OSI-027) inhibitors as compared to either drug alone [55]. The PI3K inhibitor samotolisib (LY3023414) is being tested in two ongoing clinical trials (NCT03213678 and NCT03155620) in pediatric patients with recurrent medulloblastoma [56]. Recent studies have identified GLI as a potential target for concomitant PI3K and mTOR inhibition; as a result, combined targeting of PI3K/AKT/mTOR and HH signaling may also be effective in the treatment of medulloblastoma [55]. BEZ235, a dual PI3K-mTOR inhibitor, in combination with the HH inhibitor vismodegib significantly enhanced cisplatin-mediated cytotoxicity while preferentially suppressing MYC-amplified medulloblastoma cell growth and survival [57]. Furthermore, this drug combination delayed tumor growth and prolonged survival in a xenograft rodent model of medulloblastoma with MYC amplification.

3.2.3. CDK Signaling Pathway

The CDK4/6-INK4-Rb pathway is commonly dysregulated in multiple cancers, and selective inhibition of CDK4/6 potently arrests the cell cycle of tumor cells while sparing normal cells [58,59,60]. In medulloblastoma, this pathway was identified as drug-able for all non-WNT-activated subgroups [61]. While three selective CDK4/6 inhibitors (abemaciclib, palbociclib, and ribociclib) are FDA approved for the treatment of estrogen receptor-positive metastatic breast cancer, experimental data indicate that the addition of these drugs might improve efficacy and overcome de novo or acquired treatment resistance to established therapeutic regimens in medulloblastoma [62,63]. Several clinical trials of CDK4/6 inhibitors alone or in combination with cytotoxic chemotherapy or targeted agents are ongoing. Two studies are investigating the treatment of CDK4/6 inhibitors, including palbociclib, ribociclib, or abemaciclib, in combination with temozolomide, irinotecan, topotecan, cyclophosphamide, or dinutuximab in pediatric patients with relapsed/refractory solid tumors, including medulloblastoma (NCT03709680 and NCT04238819). Another study is enrolling children and young adults with recurrent brain cancer (including group 3/group 4, WNT/SHH-activated, and SHH-activated tumors) for treatment with ribociclib in combination with gemcitabine, trametinib, or sonidegib (NCT03434262). The phase II Pediatric MATCH trial is studying the efficacy of palbociclib in patients with Rb-positive tumors (NCT03526250). A study of abemaciclib is now recruiting children and adolescents with relapsed, refractory, or progressive malignant brain tumors and solid tumors (NCT02644460).

3.2.4. Epigenetic Deregulation

In the past decade, numerous studies have revealed the key role of epigenetic dysregulation in subgroup-specific tumorigenesis of medulloblastoma [9,11,64]. Research corroborating the importance of epigenetics in medulloblastoma initiation and progression has facilitated the clinical development of novel therapeutic opportunities (Figure 1) [36,37]. A Children’s Oncology Group Phase I Consortium study reported the safety and tolerability of suberanilohydroxamic acid (SAHA)/vorinostat given in combination with temozolomide in children with refractory or recurrent CNS malignancies (NCT1076530). Three patients had stable disease and one patient had a partial response, according to the published results [65,66]. Children with recurrent or refractory solid tumors, including CNS malignancies, were enrolled in a study combining vorinostat with the proteasome inhibitor bortezomib, but the findings have not yet been published (NCT01132911). The feasibility of combining vorinostat and isotretinoin was also explored in a study of 33 participants with embryonal tumors of the CNS, including medulloblastoma patients (NCT00867178). A phase I trial (PNOC016) is presently recruiting participants to examine the effects of the HDAC/PI3K inhibitor fimepinostat on brain tumors in children and young adults (NCT03893487). The EZH2 inhibitor tazemetostat is under investigation in a phase II trial of several CNS tumors, including relapsed or progressive medulloblastoma (NCT03213665). Finally, a Pediatric Brain Tumor Consortium phase I/II study is evaluating the small molecule inhibitor of casein kinase II (CK2) silmitasertib (CX-4945) in children with recurrent SHH-activated medulloblastoma (NCT03904862). The results of these studies are eagerly awaited.

3.3. Tumor Microenvironment and Immunotherapies

There is a growing need to understand the tumor microenvironment and its role in the development and progression of medulloblastoma (Figure 3). The immune microenvironment consists of different cell types surrounding the tumor cells, including immune and non-immune cells as well as extracellularly secreted molecules, and the relationship between these can either promote or inhibit tumor growth [67]. Recent studies suggest that a lower amount of infiltrating immune cells are present in medulloblastoma than in other CNS malignancies such as glioblastoma [68,69]. Tumor-associated macrophages (TAMs) are considered the major immune cells in the medulloblastoma microenvironment and were found to be significantly more common in SHH-amplified tumors compared to other medulloblastoma subgroups [70,71]. This may be due to SHH-specific molecular signatures predictive of TAM infiltration or the high expression of monocyte chemotactic protein-1, enhancing TAM recruitment and M2 polarization [69,70,72,73]. Furthermore, glycolytic activity in response to hypoxia and acidification of the tumor microenvironment supports TAM infiltration, polarization toward an M2-like phenotype, and overexpression of programmed cell death protein ligand 1 (PD-L1) on infiltrating TAMs [74,75]. Other studies imply that the prevalence and polarization of TAMs in medulloblastoma may be age-related and associated with risk of metastatic disease and survival outcome [71,76,77,78]. Tumor-infiltrating lymphocytes (TILs) are the signaling interacting cells between TAMs and medulloblastoma cells in the tumor microenvironment. While the quantity of T cells present in medulloblastoma was not shown to be considerably higher compared to control tissues, regulatory T-cell (Treg) infiltration of the microenvironment has been described [68,69,79]. Transforming growth factor beta (TGF-β) directly inhibits CD8 T-cell activity, proliferation, and metabolism and drives differentiation of CD4 T cells to Tregs, which in turn release large amounts of TGF-β, thereby creating a feeding circuit that promotes immunosuppression [67,80,81]. Elevated levels of Tregs have been detected in the peripheral blood of patients following standard therapy, presenting a potential new strategy in the treatment of medulloblastomas [82]. However, the interaction between TAMs, TILs, other cell types, and secreted molecules in the medulloblastoma microenvironment has not been extensively studied. Further research is needed to fully elucidate the complex immune dynamics in medulloblastoma.
Due to the heterogenous nature of medulloblastoma tumors in addition to a largely non-inflammatory microenvironment with a low influx of immune cells, immunotherapeutic strategies have been challenging. The goal of immunotherapy is to stimulate and enhance the body’s natural defense system in order to slow and eventually eliminate tumor growth. Over the past 20 years, numerous immunotherapeutics have been developed for cancer treatment that have undergone intensive preclinical and clinical testing; some of these therapies have received FDA approval and are currently being used as part of innovative therapeutic regimens [83,84].
Various experimental approaches have highlighted the increasing potential for successful clinical implementation of immunotherapy (alone or in combination with alternative treatment strategies) in medulloblastoma (Figure 3) [85]. A wide spectrum of immunotherapies are in clinical development, including adoptive cellular therapy/cellular immunotherapy, immune checkpoint inhibitors, tumor vaccines, oncolytic viruses, cytokine inhibitors, and various strategies in combination with irradiation (i.e., radioimmunotherapy) [86,87,88,89,90]. Some of the major strides made in the last few years in different aspects of immunotherapy for medulloblastoma treatment are highlighted below (Table 3).

3.3.1. Adoptive Cellular Therapy/Cellular Immunotherapy

In adoptive cellular therapy, host immune cells are directly isolated, modified to improve their capacity to combat cancer, and then infused back into the host to target cancer cells [91,92]. This strategy can be applied in a variety of methods, such as NK cells, engineered T-cell receptor (TCR) therapies, chimeric antigen receptor (CAR) T cells, and tumor-infiltrating lymphocytes, some of which are in clinical testing [85,86,93].
Although originally proposed in the 1980s, CAR T cells are a relatively novel and arguably one of the most promising adoptive cellular therapy strategies for the treatment of medulloblastoma [94]. Based on genetically engineering T cells of individual patients to express a receptor that specifically binds a known tumor antigen, CAR T cells have been translated clinically and have demonstrated anti-tumor activity against glioblastoma [95,96,97,98]. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 38.5–63% of medulloblastomas, and multiple studies successfully evaluated HER2 CAR T in preclinical models of medulloblastoma with robust HER2 expression [99,100,101]. In vitro, HER2 CAR T cells showed HER2-dependent proliferation and secretion of IFN-γ and IL-2 [102]. They were highly potent in both medulloblastoma cell lines and autologous primary cells; furthermore, HER2-BBz-CAR T cells effectively induced tumor regression in orthotopic xenograft-bearing mice [102,103]. These findings were corroborated in non-human primates, in which intraventricular delivery of HER2 CAR T cells was feasible and safe [103]. A phase I study is currently investigating the loco-regional delivery of HER2-specific CAR T cells using autologous CD4+ and CD8+ T cells that were lentivirally transduced to express a HER2-specific CAR and truncated epidermal growth factor receptor (EGFRt) in HER2-positive recurrent/refractory CNS tumors, including medulloblastoma (NCT03500991). Similarly, autologous CD4+ and CD8+ T cells expressing an EGFR806 CAR and EGFRt are being tested in a phase I study of EGFR-positive pediatric CNS cancer patients (NCT03638167). Several other CAR T cells targeting NKG2D, B7-H3, GD2 or IL-13Rα2 showed promise preclinically and have now entered clinical development for medulloblastoma therapy (e.g., NCT05131763, NCT04185038, NCT05298995, and NCT04661384, respectively) [104,105,106].
Although in vivo studies showed promise with CAR T-cell therapy for preclinical medulloblastoma models that have led to several phase I clinical trials, to date, no phase II, III, or IV clinical trials have been registered to determine the clinical benefit of these treatments in medulloblastoma patients [84]. Compared to T cells, NK cells do not require specific tumor antigen recognition to kill tumor cells. Instead, they heavily rely on recognition of “induced self” and “missing self” antigen presentation to identify target cells, of which the most important host ligands include NKG2DLs (activatory) and MHC-I (inhibitory) [107]. The hostile microenvironment of medulloblastoma tumors is known to contain high levels of inhibitory molecules like TGF-β, which can inhibit NK cell function. Efforts have led to engineering NK cell lines that express a dominant-negative receptor (DNR) for TGF-β [108]. To date, only one phase I clinical trial (NCT02271711) of intracranial NK therapy for medulloblastoma patients has been completed [109].

3.3.2. Immune Checkpoint Inhibition

Immune checkpoint inhibitors are a type of immunotherapy that block immune checkpoint proteins from binding with their partner proteins. The majority of these drugs are monoclonal antibodies that work by reducing T-cell suppression and restoring function by blocking the interaction with a particular checkpoint ligand [110]. Due to their potential to cause long-lasting tumor regression, several checkpoint inhibitors have been approved by the FDA for use in different types of cancer [111,112,113,114]. Inhibitors of cytotoxic T-lymphocyte antigen 4 (CTLA-4), PD-1, or its ligand PD-L1 are among the most prominent examples to date [115]. In addition, drugs targeting newly emerging antigens, including B7 family proteins (e.g., B7-H3), CD40/CD40L, indoleamine 2,3-dioxygenase 1 (IDO1), and mucin domain 3 (TIM-3), are demonstrating encouraging results in the treatment of brain tumors in both preclinical and clinical settings [116,117,118,119,120].
The effectiveness of immune checkpoint inhibition on preclinical models of medulloblastoma has been studied by a number of groups, who found that the different molecular subgroups may have distinctive immunological profiles that respond differently to checkpoint inhibitors [119,120,121,122]. For instance, while overall levels of PD-L1 were low, SHH-activated and low-MYC-expressing tumors had higher PD-L1 expression than non-WNT/non-SHH groups 3 and 4, according to a study comparing two cohorts of human medulloblastoma tumor samples from Children’s Hospital of Philadelphia (CHOP) and Johns Hopkins Hospital, respectively [120].
Several clinical trials of checkpoint inhibitor drugs in medulloblastoma patients are ongoing. PD-1/PD-L1 inhibitors, including nivolumab, pembrolizumab, and durvalumab, are each under investigation as monotherapy in phase I/phase II studies (e.g., NCT03173950, NCT02359565, and NCT02793466). Other studies are evaluating different combinatorial regimens such as nivolumab with and without ipilimumab (NCT03130959), indoximod in combination with ibrutinib (NCT05106296), or indoximod combined with radiochemotherapy (NCT04049669). Radiolabeled B7-H3 antibodies like 131I-omburtamab have also entered clinical testing (e.g., NCT04743661 and NCT05064306).

3.3.3. Cancer Vaccination

Cancer vaccines are designed to activate an immune system that has grown tolerant to the cancer. These therapies can be categorized into multiple groups; for example whole-cell-, peptide-, DNA-, and RNA-based vaccines [123]. Tumor lysates, cells, or peptides deliver tumor antigens to antigen-presenting cells (APCs) that can then present these antigens on MHC class I and II molecules [124]. The FDA-approved sipuleucel-T vaccine consists of autologous dendritic cells that were activated with a fusion protein antigen containing a tumor-specific antigen and prostate acid phosphatase and expanded with granulocyte-macrophage colony-stimulating factor ex vivo for the treatment of prostate cancer [124,125,126]. In adult patients with newly diagnosed and recurrent glioblastoma, a phase III clinical trial recently reported clinically meaningful and statistically significant survival benefits for patients who received autologous tumor lysate-loaded dendritic cell vaccination plus the standard of care in comparison to the standard treatment alone [127,128]. This led to its evaluation in pediatric medulloblastoma. Autologous monocyte-derived dendritic cells loaded with tumor lysate for children with malignant brain tumors demonstrated that medulloblastoma responded less favorably to this therapy than high-grade gliomas and atypical/teratoid rhabdoid tumors (ATRTs) [129]. Conversely, cancer vaccines based on DNA and RNA are not restricted by HLA haplotypes, as they are transcribed and translated inside the host cells where they can then be presented to APCs to induce an immunological response [130,131,132,133,134,135]. Following proof-of-concept preclinical studies, a phase II clinical trial is currently investigating RNA-loaded autologous dendritic cells in patients with recurrent medulloblastoma and primitive neuroectodermal tumors (NCT01326104) [136]. Preliminary results were recently posted that revealed no improvement in 12-month progression-free survival in comparison to historical controls. Unfortunately, other recent clinical trials evaluating different cancer vaccine strategies in patients with medulloblastoma have been similarly unsuccessful, either lacking a robust APC response, causing severe adverse events, or failing to improve survival (NCT02332889, NCT01171469, and NCT00014573). The limited availability of viable tumor tissue for processing and vaccine generation may be partially to blame for the failure of these trials; however, the immunosuppressive nature of most medulloblastomas remains a significant hurdle for therapies that rely on the body’s own T-cell response and migration into the tumor microenvironment [86].

3.3.4. Oncolytic Virotherapy

Oncolytic viral therapy is another strategy that aims to increase immune cell recognition of cancers such as medulloblastoma [93,137,138]. In general, oncolytic viruses are biotherapeutics genetically engineered to selectively infect and eradicate tumor cells, accomplishing this through distinct two processes. First, they actively kill targeted cells by propagating inside of them and bursting them. Second, through a mechanism known as epitope spreading, tumor cell lysis exposes antigens that have shed and subsequently stimulates a systemic immune response [139,140,141]. Oncolytic viruses have been studied in a variety of cancers, including brain tumors, with encouraging preclinical and clinical results [142,143,144,145,146,147]. Medulloblastoma cell lines and primary grown cells were successfully infected in vitro with oncolytic engineered myxoma-, cytomegalo-, parvo-, and poliovirus-based therapies, which further decreased cell proliferation and induced cell death [148,149,150,151]. In vivo, recombinant oncolytic myxoma, picorna, measles, and herpes simplex viruses all showed efficacy in mouse xenograft models of orthotopic and disseminated medulloblastomas, including SHH-activated and non-WNT/non-SHH group 3 and 4 tumors, following systemic, intrathecal, or intratumoral injection, respectively [148,152,153,154,155,156]. Collectively, these findings highlight the potent preclinical anti-tumor activity of oncolytic viral therapy against medulloblastoma.
A number of oncolytic viruses have now entered early-phase clinical development in patients with medulloblastoma [93,157]. Cytomegalovirus-based vaccines in combination with a preconditioning tetanus–diphtheria toxoid vaccine are being tested in the two phase I studies NCT03299309 and NCT03615404, the latter of which recently published results demonstrating the feasibility and safety of this therapy in pediatric patients with recurrent malignant glioma and medulloblastoma. A Phase 1b trial seeks to establish the safety of oncolytic poliovirus therapy when delivered intracerebrally via convection-enhanced delivery (CED) in children with various brain tumors, including medulloblastoma (NCT03043391). Another trial is employing a modified measles virus vaccine to treat children and young adults with recurrent medulloblastoma and ATRT. The vaccine is injected directly into the primary tumor or administered via lumbar puncture in the presence of metastatic disease (NCT02962167). An intravenously delivered wild-type reovirus (pelareorep) given together with subcutaneous GM-CSF (sargramostim) is used to evaluate the side effects and the best dose of this oncolytic viral therapy in young patients with high-grade brain tumors (NCT02444546). Published results from six enrolled patients demonstrate that persistent hyponatremia was the only dose-limiting toxicity, although the maximum tolerated dose was not determined [158]. Lastly, a study evaluating the safety of an oncolytic herpes simplex virus alone or in combination with a single low dose of radiation (5 Gy) is recruiting children with recurrent or progressive cerebellar brain tumors (NCT03911388).

4. Mechanisms of Resistance

Treatment resistance in medulloblastoma presents an ongoing challenge despite the increasing molecular understanding of medulloblastoma subtypes and oncogenic drivers. Approximately 30% of patients will relapse under the current standard of care, entailing an almost universally lethal prognosis [159]. Furthermore, newly developed targeted therapies are frequently met with development of secondary resistance, limiting clinical applications [44,160].
Recently, efforts have been made to identify transcriptional, genetic, and epigenetic drivers of treatment resistance in the current standard treatment. Taylor et al. established the role of transcription factor Y-box binding protein 1 (YB-1), showing a correlation of YB-1 overexpression with multidrug pump ATP binding cassette subfamily B member 1 (ABCB1) upregulation, inducing vincristine resistance [161]. Interestingly, YB-1 overexpression also correlated with invasiveness, metastatic potential, and MYC and mTOR pathway upregulation. Furthermore, they identified a seven-gene signature (LTBP1, MAP1A, MBNL2, LGALS1, PNRC1, DAB2, and PLAAT3) that characterized cisplatin- and vincristine-tolerant group 3 and SHH cell lines, several of which also showed increased expression in post-treatment patient samples. Other molecular mechanisms, including epigenetic alterations such as loss of H3K27me3 as a marker of resistance to irradiation and differential miRNA expression, have also been implicated in therapy resistance [162,163,164]. Increasingly, these molecular drivers are being linked to reprogramming of tumor cell metabolism, enhancing aerobic glycolysis, lipogenesis, and glutamine metabolism, which correlates with increased resilience to chemotherapy [164,165]. However, literature regarding the molecular drivers of resistance is scarce, and the interplay between these mechanisms remains to be elucidated.
On a cellular level, another mechanism of resistance in medulloblastoma is the existence of cancer stem cells (CSCs), a cell population exhibiting enhanced tumorigenesis, invasiveness, and resistance to standard chemoradiotherapy [166]. The inability to eradicate CSCs with the current standard treatment regimens allows for tumor recurrence, resulting in a tumor cell population of the same molecular subgroup but often enriched in TP3-pathway- and apoptosis-related gene alterations, resulting in therapy resistance [167,168,169,170]. A well-established CSC marker is CD133 (promenin-1), a known predictor of poor survival in medulloblastoma that is associated with resistance to both chemotherapy and radiotherapy [166,171,172,173]. Other CSC-like populations have been identified in SHH medulloblastoma mouse models expressing Nestin, Olig2, and/or Sox2 [170,174]. These populations, which resemble Nestin-expressing granule precursor cells, have been shown to be more resistant to radiotherapy by resisting p53-pathway activation [170]. Although largely quiescent pretreatment, they proliferate rapidly upon RT and/or chemotherapy, at least in part through activation of the PI3K/AKT/mTOR pathway, thereby driving tumor recurrence [55,174,175]. Recently, advancements in metabolomic strategies have allowed for the detection of CSCs according to their metabolic signature, providing novel strategies for the identification and targeting of these cells [165].
Considering that the failure of progenitor stem cells to differentiate during hindbrain maturation is thought to be the cause of medulloblastoma, CSCs are likely to coincide with the medulloblastoma cells of origin [176]. WNT signaling activation in the lower rhombic lip progenitor cells causes WNT-activated medulloblastoma, while upregulated SHH signaling in the cerebellar granule neuron precursors of the external granule cell layer leads to SHH medulloblastoma [177,178,179]. Although non-WNT/non-SHH group 3 and group 4 medulloblastoma remain the least understood, recently the unipolar brush cell progenitor in the subventricular zone of the upper rhombic lip has been put forward as the cell of origin of group 4 medulloblastoma (despite some medulloblastoma cells also showing transcriptional resemblance to granule neuron precursor cells), whereas group 3 medulloblastoma seems to arise from earlier, undifferentiated progenitor cells [176,180,181]. With different progenitor cells giving rise to medulloblastoma subgroups, different CSC populations could correlate with the distinct relapse rates and patterns [166]. Many of the characteristic pathways (e.g., the WNT pathway, SHH pathways, and MYC amplification) are related to stemness and are increasingly being evaluated as therapeutic targets, especially in SHH and group 3 tumors [33]. However, specifically targeting a single pathway often results in the development of secondary resistance through clonal selection or escape pathway upregulation, leading to a highly variable and often transient response [41,42,45]. For example, using the SMO inhibitor vismodegib, mutations in the binding pocket of SMO have been shown upon treatment, leading to an inability to exert its therapeutic effect [44]. Furthermore, patients with downstream SHH-pathway alterations such as SUFU and MYCN/GLI2 amplifications do not respond to SMO inhibition [44,45]. Moreover, while several mTOR inhibitors have been evaluated, IDO1-mediated immune escape and Mnk2-mediated eIF4E pathway activation have been shown to limit effectiveness in medulloblastoma [182,183].
Notwithstanding the progressive unraveling of the molecular underpinnings in medulloblastoma, the molecular drivers of treatment resistance remain poorly understood. However, potentially targetable mechanisms are increasingly being identified, and although targeting a single pathway almost invariably leads to resistance, further evaluation of rationally designed combination therapies could provide novel therapeutic options in treatment-resistant medulloblastoma. Furthermore, the deepened understanding of the cells of origin of the medulloblastoma subtypes has rekindled the old hypothesis that collections of atypical cells regularly detected in the postnatal nodulus could represent precursory lesions to certain medulloblastoma subtypes [184]. Hendrikse et al., in proposing the name “persistent rhombic lip” (PeRL, as opposed to the earlier “cerebellar heterotopias”), postulated that early detection and monitoring of these cells could even enable early intervention, possibly preventing group 3 or 4 medulloblastoma in the future [179].

5. Conclusions

Despite major advancements in cancer genomics and molecular diagnostics over the past decades, surgical resection, irradiation, and adjuvant chemotherapy generally remain the standard of care for all medulloblastoma subgroups. This has several significant shortcomings, including short- and long-term side effects. Major efforts have been made to identify subgroup-specific gene mutations and amplifications as potential targets for customized therapeutic methods, with some of them being tested in clinical trials. Immunotherapy has emerged as another promising avenue in medulloblastoma treatment, whereby adoptive cellular therapy and checkpoint inhibition are the frontrunners of a vast array of diverse immunotherapeutic strategies in preclinical and clinical testing. Understanding the tumor microenvironment of medulloblastoma and the interactions between different cell types could provide valuable insights into mechanisms of resistance and potentially lead to new targeted therapies. Furthermore, the deepened understanding of the cells of origin giving rise to distinct medulloblastoma subtypes—most likely coinciding with CSCs driving tumor recurrence—potentially allows for the development of therapies to eradicate these cells specifically or even early, presymptomatic detection and interventions. Future medulloblastoma research will profile personalized treatments for each individual patient based on molecular risk stratification of the disease with the hope of improving survival and reducing relapses.

Author Contributions

Conception and design: J.S.R., S.A.T., W.J.F.V. and S.K.; drafting the article: J.S.R., S.A.T. and W.J.F.V.; critically revising the article: D.J.D. and S.K.; reviewed submitted version of manuscript: J.S.R., S.A.T., W.J.F.V., D.J.D. and S.K.; approved the final version of the manuscript on behalf of all authors: J.S.R., W.J.F.V. and S.K.; article supervision: D.J.D. and S.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

No individuals other than the listed co-authors contributed to this publication. Figures were created with BioRender.com (accessed on 1 May 2023).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Louis, D.N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.; Kleihues, P.; Ellison, D.W. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary. Acta Neuropathol. 2016, 131, 803–820. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Louis, D.N.; Perry, A.; Wesseling, P.; Brat, D.J.; Cree, I.A.; Figarella-Branger, D.; Hawkins, C.; Ng, H.K.; Pfister, S.M.; Reifenberger, G.; et al. The 2021 WHO Classification of Tumors of the Central Nervous System: A summary. Neuro Oncol. 2021, 23, 1231–1251. [Google Scholar] [CrossRef] [PubMed]
  3. Cotter, J.A.; Hawkins, C. Medulloblastoma: WHO 2021 and beyond. Pediatr. Dev. Pathol. 2022, 25, 23–33. [Google Scholar] [CrossRef] [PubMed]
  4. Schwalbe, E.C.; Lindsey, J.C.; Nakjang, S.; Crosier, S.; Smith, A.J.; Hicks, D.; Rafiee, G.; Hill, R.M.; Iliasova, A.; Stone, T.; et al. Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: A cohort study. Lancet Oncol. 2017, 18, 958–971. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Zhukova, N.; Ramaswamy, V.; Remke, M.; Pfaff, E.; Shih, D.J.; Martin, D.C.; Castelo-Branco, P.; Baskin, B.; Ray, P.N.; Bouffet, E.; et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J. Clin. Oncol. 2013, 31, 2927–2935. [Google Scholar] [CrossRef] [Green Version]
  6. Cavalli, F.M.G.; Remke, M.; Rampasek, L.; Peacock, J.; Shih, D.J.H.; Luu, B.; Garzia, L.; Torchia, J.; Nor, C.; Morrissy, A.S.; et al. Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell 2017, 31, 737–754.E6. [Google Scholar] [CrossRef] [Green Version]
  7. Gorini, F.; Miceli, M.; de Antonellis, P.; Amente, S.; Zollo, M.; Ferrucci, V. Epigenetics and immune cells in medulloblastoma. Front. Genet. 2023, 14, 1135404. [Google Scholar] [CrossRef]
  8. Pugh, T.J.; Weeraratne, S.D.; Archer, T.C.; Pomeranz Krummel, D.A.; Auclair, D.; Bochicchio, J.; Carneiro, M.O.; Carter, S.L.; Cibulskis, K.; Erlich, R.L.; et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 2012, 488, 106–110. [Google Scholar] [CrossRef] [Green Version]
  9. Yi, J.; Wu, J. Epigenetic regulation in medulloblastoma. Mol. Cell. Neurosci. 2018, 87, 65–76. [Google Scholar] [CrossRef]
  10. Jones, P.A.; Baylin, S.B. The epigenomics of cancer. Cell 2007, 128, 683–692. [Google Scholar] [CrossRef] [Green Version]
  11. Haltom, A.R.; Toll, S.A.; Cheng, D.; Maegawa, S.; Gopalakrishnan, V.; Khatua, S. Medulloblastoma epigenetics and the path to clinical innovation. J. Neurooncol. 2020, 150, 35–46. [Google Scholar] [CrossRef] [PubMed]
  12. Schwalbe, E.C.; Williamson, D.; Lindsey, J.C.; Hamilton, D.; Ryan, S.L.; Megahed, H.; Garami, M.; Hauser, P.; Dembowska-Baginska, B.; Perek, D.; et al. DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. Acta Neuropathol. 2013, 125, 359–371. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Lusher, M.E.; Lindsey, J.C.; Latif, F.; Pearson, A.D.; Ellison, D.W.; Clifford, S.C. Biallelic epigenetic inactivation of the RASSF1A tumor suppressor gene in medulloblastoma development. Cancer Res. 2002, 62, 5906–5911. [Google Scholar] [PubMed]
  14. Zuzak, T.J.; Steinhoff, D.F.; Sutton, L.N.; Phillips, P.C.; Eggert, A.; Grotzer, M.A. Loss of caspase-8 mRNA expression is common in childhood primitive neuroectodermal brain tumour/medulloblastoma. Eur. J. Cancer. 2002, 38, 83–91. [Google Scholar] [CrossRef] [PubMed]
  15. Rood, B.R.; Zhang, H.; Weitman, D.M.; Cogen, P.H. Hypermethylation of HIC-1 and 17p allelic loss in medulloblastoma. Cancer Res. 2002, 62, 3794–3797. [Google Scholar]
  16. Pfister, S.; Schlaeger, C.; Mendrzyk, F.; Wittmann, A.; Benner, A.; Kulozik, A.; Scheurlen, W.; Radlwimmer, B.; Lichter, P. Array-based profiling of reference-independent methylation status (aPRIMES) identifies frequent promoter methylation and consecutive downregulation of ZIC2 in pediatric medulloblastoma. Nucleic Acids Res. 2007, 35, e51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Lindsey, J.C.; Kawauchi, D.; Schwalbe, E.C.; Solecki, D.J.; Selby, M.P.; McKinnon, P.J.; Olson, J.M.; Hayden, J.T.; Grundy, R.G.; Ellison, D.W.; et al. Cross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance. Oncogene 2015, 34, 4746–4757. [Google Scholar] [CrossRef] [Green Version]
  18. Lindsey, J.C.; Lusher, M.E.; Anderton, J.A.; Gilbertson, R.J.; Ellison, D.W.; Clifford, S.C. Epigenetic deregulation of multiple S100 gene family members by differential hypomethylation and hypermethylation events in medulloblastoma. Br. J. Cancer 2007, 97, 267–274. [Google Scholar] [CrossRef] [Green Version]
  19. Hovestadt, V.; Jones, D.T.; Picelli, S.; Wang, W.; Kool, M.; Northcott, P.A.; Sultan, M.; Stachurski, K.; Ryzhova, M.; Warnatz, H.J.; et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 2014, 510, 537–541. [Google Scholar] [CrossRef] [Green Version]
  20. Northcott, P.A.; Nakahara, Y.; Wu, X.; Feuk, L.; Ellison, D.W.; Croul, S.; Mack, S.; Kongkham, P.N.; Peacock, J.; Dubuc, A.; et al. Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat. Genet. 2009, 41, 465–472. [Google Scholar] [CrossRef] [Green Version]
  21. Batora, N.V.; Sturm, D.; Jones, D.T.; Kool, M.; Pfister, S.M.; Northcott, P.A. Transitioning from genotypes to epigenotypes: Why the time has come for medulloblastoma epigenomics. Neuroscience 2014, 264, 171–185. [Google Scholar] [CrossRef]
  22. Dubuc, A.M.; Remke, M.; Korshunov, A.; Northcott, P.A.; Zhan, S.H.; Mendez-Lago, M.; Kool, M.; Jones, D.T.; Unterberger, A.; Morrissy, A.S.; et al. Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathol. 2013, 125, 373–384. [Google Scholar] [CrossRef] [Green Version]
  23. Pfister, S.; Rea, S.; Taipale, M.; Mendrzyk, F.; Straub, B.; Ittrich, C.; Thuerigen, O.; Sinn, H.P.; Akhtar, A.; Lichter, P. The histone acetyltransferase hMOF is frequently downregulated in primary breast carcinoma and medulloblastoma and constitutes a biomarker for clinical outcome in medulloblastoma. Int. J. Cancer 2008, 122, 1207–1213. [Google Scholar] [CrossRef] [PubMed]
  24. Northcott, P.A.; Buchhalter, I.; Morrissy, A.S.; Hovestadt, V.; Weischenfeldt, J.; Ehrenberger, T.; Grobner, S.; Segura-Wang, M.; Zichner, T.; Rudneva, V.A.; et al. The whole-genome landscape of medulloblastoma subtypes. Nature 2017, 547, 311–317. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Genovesi, L.A.; Carter, K.W.; Gottardo, N.G.; Giles, K.M.; Dallas, P.B. Integrated analysis of miRNA and mRNA expression in childhood medulloblastoma compared with neural stem cells. PLoS ONE 2011, 6, e23935. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Mollashahi, B.; Aghamaleki, F.S.; Movafagh, A. The Roles of miRNAs in Medulloblastoma: A Systematic Review. J. Cancer Prev. 2019, 24, 79–90. [Google Scholar] [CrossRef]
  27. Ferretti, E.; De Smaele, E.; Po, A.; Di Marcotullio, L.; Tosi, E.; Espinola, M.S.; Di Rocco, C.; Riccardi, R.; Giangaspero, F.; Farcomeni, A.; et al. MicroRNA profiling in human medulloblastoma. Int. J. Cancer 2009, 124, 568–577. [Google Scholar] [CrossRef]
  28. Leary, S.E.S.; Packer, R.J.; Li, Y.; Billups, C.A.; Smith, K.S.; Jaju, A.; Heier, L.; Burger, P.; Walsh, K.; Han, Y.; et al. Efficacy of Carboplatin and Isotretinoin in Children with High-risk Medulloblastoma: A Randomized Clinical Trial from the Children’s Oncology Group. JAMA Oncol. 2021, 7, 1313–1321. [Google Scholar] [CrossRef]
  29. Northcott, P.A.; Jones, D.T.; Kool, M.; Robinson, G.W.; Gilbertson, R.J.; Cho, Y.J.; Pomeroy, S.L.; Korshunov, A.; Lichter, P.; Taylor, M.D.; et al. Medulloblastomics: The end of the beginning. Nat. Rev. Cancer 2012, 12, 818–834. [Google Scholar] [CrossRef] [Green Version]
  30. Clifford, S.C.; Lusher, M.E.; Lindsey, J.C.; Langdon, J.A.; Gilbertson, R.J.; Straughton, D.; Ellison, D.W. Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis. Cell Cycle 2006, 5, 2666–2670. [Google Scholar] [CrossRef] [Green Version]
  31. Ellison, D.W.; Kocak, M.; Dalton, J.; Megahed, H.; Lusher, M.E.; Ryan, S.L.; Zhao, W.; Nicholson, S.L.; Taylor, R.E.; Bailey, S.; et al. Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J. Clin. Oncol. 2011, 29, 1400–1407. [Google Scholar] [CrossRef] [Green Version]
  32. Ellison, D.W.; Onilude, O.E.; Lindsey, J.C.; Lusher, M.E.; Weston, C.L.; Taylor, R.E.; Pearson, A.D.; Clifford, S.C. beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: The United Kingdom Children’s Cancer Study Group Brain Tumour Committee. J. Clin. Oncol. 2005, 23, 7951–7957. [Google Scholar] [CrossRef]
  33. Maier, H.; Dalianis, T.; Kostopoulou, O.N. New Approaches in Targeted Therapy for Medulloblastoma in Children. Anticancer Res. 2021, 41, 1715–1726. [Google Scholar] [CrossRef] [PubMed]
  34. Schultz, K.A.; Ness, K.K.; Whitton, J.; Recklitis, C.; Zebrack, B.; Robison, L.L.; Zeltzer, L.; Mertens, A.C. Behavioral and social outcomes in adolescent survivors of childhood cancer: A report from the childhood cancer survivor study. J. Clin. Oncol. 2007, 25, 3649–3656. [Google Scholar] [CrossRef] [PubMed]
  35. Ness, K.K.; Gurney, J.G.; Zeltzer, L.K.; Leisenring, W.; Mulrooney, D.A.; Nathan, P.C.; Robison, L.L.; Mertens, A.C. The impact of limitations in physical, executive, and emotional function on health-related quality of life among adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Arch. Phys. Med. Rehabil. 2008, 89, 128–136. [Google Scholar] [CrossRef]
  36. Thompson, E.M.; Ashley, D.; Landi, D. Current medulloblastoma subgroup specific clinical trials. Transl. Pediatr. 2020, 9, 157–162. [Google Scholar] [CrossRef]
  37. Liu, X.; Ding, C.; Tan, W.; Zhang, A. Medulloblastoma: Molecular understanding, treatment evolution, and new developments. Pharmacol. Ther. 2020, 210, 107516. [Google Scholar] [CrossRef]
  38. Khatua, S.; Song, A.; Citla Sridhar, D.; Mack, S.C. Childhood Medulloblastoma: Current Therapies, Emerging Molecular Landscape and Newer Therapeutic Insights. Curr. Neuropharmacol. 2018, 16, 1045–1058. [Google Scholar] [CrossRef]
  39. Pak, E.; Segal, R.A. Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy. Dev. Cell 2016, 38, 333–344. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Petrirena, G.J.; Masliah-Planchon, J.; Sala, Q.; Pourroy, B.; Frappaz, D.; Tabouret, E.; Graillon, T.; Gentet, J.-C.; Delattre, O.; Chinot, O.; et al. Recurrent extraneural sonic hedgehog medulloblastoma exhibiting sustained response to vismodegib and temozolomide monotherapies and inter-metastatic molecular heterogeneity at progression. Oncotarget 2018, 9, 10175–10183. [Google Scholar] [CrossRef] [Green Version]
  41. Rudin, C.M.; Hann, C.L.; Laterra, J.; Yauch, R.L.; Callahan, C.A.; Fu, L.; Holcomb, T.; Stinson, J.; Gould, S.E.; Coleman, B.; et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N. Engl. J. Med. 2009, 361, 1173–1178. [Google Scholar] [CrossRef] [Green Version]
  42. Robinson, G.W.; Orr, B.A.; Wu, G.; Gururangan, S.; Lin, T.; Qaddoumi, I.; Packer, R.J.; Goldman, S.; Prados, M.D.; Desjardins, A.; et al. Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results from Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032. J. Clin. Oncol. 2015, 33, 2646–2654. [Google Scholar] [CrossRef] [PubMed]
  43. Kool, M.; Jones, D.T.; Jäger, N.; Northcott, P.A.; Pugh, T.J.; Hovestadt, V.; Piro, R.M.; Esparza, L.A.; Markant, S.L.; Remke, M.; et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 2014, 25, 393–405. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Robinson, G.W.; Kaste, S.C.; Chemaitilly, W.; Bowers, D.C.; Laughton, S.; Smith, A.; Gottardo, N.G.; Partap, S.; Bendel, A.; Wright, K.D.; et al. Irreversible growth plate fusions in children with medulloblastoma treated with a targeted hedgehog pathway inhibitor. Oncotarget 2017, 8, 69295–69302. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Kieran, M.W.; Chisholm, J.; Casanova, M.; Brandes, A.A.; Aerts, I.; Bouffet, E.; Bailey, S.; Leary, S.; MacDonald, T.J.; Mechinaud, F.; et al. Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma. Neuro Oncol. 2017, 19, 1542–1552. [Google Scholar] [CrossRef]
  46. Yuile, A.K.; Kastelan, M.; Lee, A.P.; Back, M.; Drummond, J.; Wheeler, H.R. The use of Sonidegib in the adjuvant and advanced phases of Sonic Hedge Hog Mutant Medulloblastomas. Oxf. Med. Case Rep. 2022, 2022, omac019. [Google Scholar] [CrossRef]
  47. Infante, P.; Alfonsi, R.; Botta, B.; Mori, M.; Di Marcotullio, L. Targeting GLI factors to inhibit the Hedgehog pathway. Trends Pharmacol. Sci. 2015, 36, 547–558. [Google Scholar] [CrossRef] [Green Version]
  48. Coni, S.; Antonucci, L.; D’Amico, D.; Di Magno, L.; Infante, P.; De Smaele, E.; Giannini, G.; Di Marcotullio, L.; Screpanti, I.; Gulino, A.; et al. Gli2 acetylation at lysine 757 regulates hedgehog-dependent transcriptional output by preventing its promoter occupancy. PLoS ONE 2013, 8, e65718. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. De Braganca, K.C.; Packer, R.J. Treatment Options for Medulloblastoma and CNS Primitive Neuroectodermal Tumor (PNET). Curr. Treat. Options Neurol. 2013, 15, 593–606. [Google Scholar] [CrossRef] [Green Version]
  50. Holzhauser, S.; Lukoseviciute, M.; Andonova, T.; Ursu, R.G.; Dalianis, T.; Wickström, M.; Kostopoulou, O.N. Targeting Fibroblast Growth Factor Receptor (FGFR) and Phosphoinositide 3-kinase (PI3K) Signaling Pathways in Medulloblastoma Cell Lines. Anticancer Res. 2020, 40, 53–66. [Google Scholar] [CrossRef]
  51. Yuan, T.L.; Cantley, L.C. PI3K pathway alterations in cancer: Variations on a theme. Oncogene 2008, 27, 5497–5510. [Google Scholar] [CrossRef] [Green Version]
  52. Holzhauser, S.; Lukoseviciute, M.; Papachristofi, C.; Vasilopoulou, C.; Herold, N.; Wickström, M.; Kostopoulou, O.N.; Dalianis, T. Effects of PI3K and FGFR inhibitors alone and in combination, and with/without cytostatics in childhood neuroblastoma cell lines. Int. J. Oncol. 2021, 58, 211–225. [Google Scholar] [CrossRef] [PubMed]
  53. Hambardzumyan, D.; Becher, O.J.; Rosenblum, M.K.; Pandolfi, P.P.; Manova-Todorova, K.; Holland, E.C. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 2008, 22, 436–448. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Eckerdt, F.; Clymer, J.; Bell, J.B.; Beauchamp, E.M.; Blyth, G.T.; Goldman, S.; Platanias, L.C. Pharmacological mTOR targeting enhances the antineoplastic effects of selective PI3Kα inhibition in medulloblastoma. Sci. Rep. 2019, 9, 12822. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Parsons, D.W.; Janeway, K.A.; Patton, D.R.; Winter, C.L.; Coffey, B.; Williams, P.M.; Roy-Chowdhuri, S.; Tsongalis, G.J.; Routbort, M.; Ramirez, N.C.; et al. Actionable Tumor Alterations and Treatment Protocol Enrollment of Pediatric and Young Adult Patients with Refractory Cancers in the National Cancer Institute-Children’s Oncology Group Pediatric MATCH Trial. J. Clin. Oncol. 2022, 40, 2224–2234. [Google Scholar] [CrossRef] [PubMed]
  56. Chaturvedi, N.K.; Kling, M.J.; Coulter, D.W.; McGuire, T.R.; Ray, S.; Kesherwani, V.; Joshi, S.S.; Sharp, J.G. Improved therapy for medulloblastoma: Targeting hedgehog and PI3K-mTOR signaling pathways in combination with chemotherapy. Oncotarget 2018, 9, 16619–16633. [Google Scholar] [CrossRef] [Green Version]
  57. Northcott, P.A.; Shih, D.J.; Peacock, J.; Garzia, L.; Morrissy, A.S.; Zichner, T.; Stütz, A.M.; Korshunov, A.; Reimand, J.; Schumacher, S.E.; et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 2012, 488, 49–56. [Google Scholar] [CrossRef] [Green Version]
  58. Shapiro, G.I. Cyclin-dependent kinase pathways as targets for cancer treatment. J. Clin. Oncol. 2006, 24, 1770–1783. [Google Scholar] [CrossRef] [Green Version]
  59. Roberts, P.J.; Bisi, J.E.; Strum, J.C.; Combest, A.J.; Darr, D.B.; Usary, J.E.; Zamboni, W.C.; Wong, K.K.; Perou, C.M.; Sharpless, N.E. Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J. Natl. Cancer Inst. 2012, 104, 476–487. [Google Scholar] [CrossRef] [Green Version]
  60. Cook Sangar, M.L.; Genovesi, L.A.; Nakamoto, M.W.; Davis, M.J.; Knobluagh, S.E.; Ji, P.; Millar, A.; Wainwright, B.J.; Olson, J.M. Inhibition of CDK4/6 by Palbociclib Significantly Extends Survival in Medulloblastoma Patient-Derived Xenograft Mouse Models. Clin. Cancer Res. 2017, 23, 5802–5813. [Google Scholar] [CrossRef]
  61. Roberts, P.J.; Kumarasamy, V.; Witkiewicz, A.K.; Knudsen, E.S. Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows. Mol. Cancer Ther. 2020, 19, 1575–1588. [Google Scholar] [CrossRef]
  62. Whiteway, S.L.; Harris, P.S.; Venkataraman, S.; Alimova, I.; Birks, D.K.; Donson, A.M.; Foreman, N.K.; Vibhakar, R. Inhibition of cyclin-dependent kinase 6 suppresses cell proliferation and enhances radiation sensitivity in medulloblastoma cells. J. Neurooncol. 2013, 111, 113–121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Roussel, M.F.; Stripay, J.L. Epigenetic Drivers in Pediatric Medulloblastoma. Cerebellum 2018, 17, 28–36. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Fouladi, M.; Park, J.R.; Stewart, C.F.; Gilbertson, R.J.; Schaiquevich, P.; Sun, J.; Reid, J.M.; Ames, M.M.; Speights, R.; Ingle, A.M.; et al. Pediatric phase I trial and pharmacokinetic study of vorinostat: A Children’s Oncology Group phase I consortium report. J. Clin. Oncol. 2010, 28, 3623–3629. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Hummel, T.R.; Wagner, L.; Ahern, C.; Fouladi, M.; Reid, J.M.; McGovern, R.M.; Ames, M.M.; Gilbertson, R.J.; Horton, T.; Ingle, A.M.; et al. A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: A Children’s Oncology Group phase 1 consortium study. Pediatr. Blood Cancer 2013, 60, 1452–1457. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Quail, D.F.; Joyce, J.A. The Microenvironmental Landscape of Brain Tumors. Cancer Cell 2017, 31, 326–341. [Google Scholar] [CrossRef] [Green Version]
  67. Griesinger, A.M.; Birks, D.K.; Donson, A.M.; Amani, V.; Hoffman, L.M.; Waziri, A.; Wang, M.; Handler, M.H.; Foreman, N.K. Characterization of distinct immunophenotypes across pediatric brain tumor types. J. Immunol. 2013, 191, 4880–4888. [Google Scholar] [CrossRef] [Green Version]
  68. Bockmayr, M.; Mohme, M.; Klauschen, F.; Winkler, B.; Budczies, J.; Rutkowski, S.; Schüller, U. Subgroup-specific immune and stromal microenvironment in medulloblastoma. Oncoimmunology 2018, 7, e1462430. [Google Scholar] [CrossRef] [Green Version]
  69. Margol, A.S.; Robison, N.J.; Gnanachandran, J.; Hung, L.T.; Kennedy, R.J.; Vali, M.; Dhall, G.; Finlay, J.L.; Erdreich-Epstein, A.; Krieger, M.D.; et al. Tumor-associated macrophages in SHH subgroup of medulloblastomas. Clin. Cancer Res. 2015, 21, 1457–1465. [Google Scholar] [CrossRef] [Green Version]
  70. Zhang, J.; Yuan, X.; Wang, Y.; Liu, J.; Li, Z.; Li, S.; Liu, Y.; Gong, X.; Sun, Y.; Wu, W.; et al. Tumor-Associated Macrophages Correlate with Prognosis in Medulloblastoma. Front. Oncol. 2022, 12, 893132. [Google Scholar] [CrossRef]
  71. O’Connor, T.; Heikenwalder, M. CCL2 in the Tumor Microenvironment. In Tumor Microenvironment; Advances in Experimental Medicine and Biology; Springer: Berlin/Heidelberg, Germany, 2021; Volume 1302, pp. 1–14. [Google Scholar] [CrossRef]
  72. Maximov, V.; Chen, Z.; Wei, Y.; Robinson, M.H.; Herting, C.J.; Shanmugam, N.S.; Rudneva, V.A.; Goldsmith, K.C.; MacDonald, T.J.; Northcott, P.A.; et al. Tumour-associated macrophages exhibit anti-tumoural properties in Sonic Hedgehog medulloblastoma. Nat. Commun. 2019, 10, 2410. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Colegio, O.R.; Chu, N.Q.; Szabo, A.L.; Chu, T.; Rhebergen, A.M.; Jairam, V.; Cyrus, N.; Brokowski, C.E.; Eisenbarth, S.C.; Phillips, G.M.; et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 2014, 513, 559–563. [Google Scholar] [CrossRef] [Green Version]
  74. Noman, M.Z.; Desantis, G.; Janji, B.; Hasmim, M.; Karray, S.; Dessen, P.; Bronte, V.; Chouaib, S. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 2014, 211, 781–790. [Google Scholar] [CrossRef]
  75. Crotty, E.E.; Smith, S.M.C.; Brasel, K.; Pakiam, F.; Girard, E.J.; Connor, Y.D.; Zindy, F.; Mhyre, A.J.; Roussel, M.F.; Olson, J.M. Medulloblastoma recurrence and metastatic spread are independent of colony-stimulating factor 1 receptor signaling and macrophage survival. J. Neurooncol. 2021, 153, 225–237. [Google Scholar] [CrossRef]
  76. Lee, C.; Lee, J.; Choi, S.A.; Kim, S.K.; Wang, K.C.; Park, S.H.; Kim, S.H.; Lee, J.Y.; Phi, J.H. M1 macrophage recruitment correlates with worse outcome in SHH Medulloblastomas. BMC Cancer 2018, 18, 535. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Patt, S.; Zimmer, C. Age-related immunoreactivity pattern in medulloblastoma. Child’s Nerv. Syst. 1992, 8, 326–331. [Google Scholar] [CrossRef]
  78. Haberthur, K.; Brennan, K.; Hoglund, V.; Balcaitis, S.; Chinn, H.; Davis, A.; Kreuser, S.; Winter, C.; Leary, S.E.; Deutsch, G.H.; et al. NKG2D ligand expression in pediatric brain tumors. Cancer Biol. Ther. 2016, 17, 1253–1265. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Kurdi, M.; Mulla, N.; Malibary, H.; Bamaga, A.K.; Fadul, M.M.; Faizo, E.; Hakamy, S.; Baeesa, S. Immune microenvironment of medulloblastoma: The association between its molecular subgroups and potential targeted immunotherapeutic receptors. World J. Clin. Oncol. 2023, 14, 117–130. [Google Scholar] [CrossRef]
  80. Ye, X.Z.; Xu, S.L.; Xin, Y.H.; Yu, S.C.; Ping, Y.F.; Chen, L.; Xiao, H.L.; Wang, B.; Yi, L.; Wang, Q.L.; et al. Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-β1 signaling pathway. J. Immunol. 2012, 189, 444–453. [Google Scholar] [CrossRef] [Green Version]
  81. Gururangan, S.; Reap, E.; Schmittling, R.; Kocak, M.; Reynolds, R.; Grant, G.; Onar-Thomas, A.; Baxter, P.; Pollack, I.F.; Phillips, P.; et al. Regulatory T cell subsets in patients with medulloblastoma at diagnosis and during standard irradiation and chemotherapy (PBTC N-11). Cancer Immunol. Immunother. 2017, 66, 1589–1595. [Google Scholar] [CrossRef]
  82. Esfahani, K.; Roudaia, L.; Buhlaiga, N.; Del Rincon, S.V.; Papneja, N.; Miller, W.H., Jr. A review of cancer immunotherapy: From the past, to the present, to the future. Curr. Oncol. 2020, 27, S87–S97. [Google Scholar] [CrossRef] [PubMed]
  83. Schakelaar, M.Y.; Monnikhof, M.; Crnko, S.; Pijnappel, E.W.; Meeldijk, J.; Ten Broeke, T.; Bovenschen, N. Cellular immunotherapy for medulloblastoma. Neuro Oncol. 2023, 25, 617–627. [Google Scholar] [CrossRef]
  84. Voskamp, M.J.; Li, S.; van Daalen, K.R.; Crnko, S.; Ten Broeke, T.; Bovenschen, N. Immunotherapy in Medulloblastoma: Current State of Research, Challenges, and Future Perspectives. Cancers 2021, 13, 5387. [Google Scholar] [CrossRef] [PubMed]
  85. Audi, Z.F.; Saker, Z.; Rizk, M.; Harati, H.; Fares, Y.; Bahmad, H.F.; Nabha, S.M. Immunosuppression in Medulloblastoma: Insights into Cancer Immunity and Immunotherapy. Curr. Treat. Options Oncol. 2021, 22, 83. [Google Scholar] [CrossRef]
  86. Ward, S.A.; Warrington, N.M.; Taylor, S.; Kfoury, N.; Luo, J.; Rubin, J.B. Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4. Cancer Res. 2017, 77, 1416–1426. [Google Scholar] [CrossRef] [Green Version]
  87. Reits, E.A.; Hodge, J.W.; Herberts, C.A.; Groothuis, T.A.; Chakraborty, M.; Wansley, E.K.; Camphausen, K.; Luiten, R.M.; de Ru, A.H.; Neijssen, J.; et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 2006, 203, 1259–1271. [Google Scholar] [CrossRef] [PubMed]
  88. Vermeer, D.W.; Spanos, W.C.; Vermeer, P.D.; Bruns, A.M.; Lee, K.M.; Lee, J.H. Radiation-induced loss of cell surface CD47 enhances immune-mediated clearance of human papillomavirus-positive cancer. Int. J. Cancer 2013, 133, 120–129. [Google Scholar] [CrossRef] [Green Version]
  89. Das, A.; McDonald, D.; Lowe, S.; Bredlau, A.L.; Vanek, K.; Patel, S.J.; Cheshier, S.; Eskandari, R. Immunological low-dose radiation modulates the pediatric medulloblastoma antigens and enhances antibody-dependent cellular cytotoxicity. Child’s Nerv. Syst. 2017, 33, 429–436. [Google Scholar] [CrossRef]
  90. Wang, Z.; Cao, Y.J. Adoptive Cell Therapy Targeting Neoantigens: A Frontier for Cancer Research. Front. Immunol. 2020, 11, 176. [Google Scholar] [CrossRef] [Green Version]
  91. Ligon, J.A.; Wessel, K.M.; Shah, N.N.; Glod, J. Adoptive Cell Therapy in Pediatric and Young Adult Solid Tumors: Current Status and Future Directions. Front. Immunol. 2022, 13, 846346. [Google Scholar] [CrossRef]
  92. Kabir, T.F.; Kunos, C.A.; Villano, J.L.; Chauhan, A. Immunotherapy for Medulloblastoma: Current Perspectives. ImmunoTargets Ther. 2020, 9, 57–77. [Google Scholar] [CrossRef] [Green Version]
  93. Gross, G.; Waks, T.; Eshhar, Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc. Natl. Acad. Sci. USA 1989, 86, 10024–10028. [Google Scholar] [CrossRef]
  94. Brown, C.E.; Alizadeh, D.; Starr, R.; Weng, L.; Wagner, J.R.; Naranjo, A.; Ostberg, J.R.; Blanchard, M.S.; Kilpatrick, J.; Simpson, J.; et al. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. N. Engl. J. Med. 2016, 375, 2561–2569. [Google Scholar] [CrossRef]
  95. Ahmed, N.; Brawley, V.; Hegde, M.; Bielamowicz, K.; Kalra, M.; Landi, D.; Robertson, C.; Gray, T.L.; Diouf, O.; Wakefield, A.; et al. HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial. JAMA Oncol. 2017, 3, 1094–1101. [Google Scholar] [CrossRef] [PubMed]
  96. Brown, C.E.; Aguilar, B.; Starr, R.; Yang, X.; Chang, W.C.; Weng, L.; Chang, B.; Sarkissian, A.; Brito, A.; Sanchez, J.F.; et al. Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma. Mol. Ther. 2018, 26, 31–44. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Akhavan, D.; Alizadeh, D.; Wang, D.; Weist, M.R.; Shepphird, J.K.; Brown, C.E. CAR T cells for brain tumors: Lessons learned and road ahead. Immunol. Rev. 2019, 290, 60–84. [Google Scholar] [CrossRef] [Green Version]
  98. Gajjar, A.; Hernan, R.; Kocak, M.; Fuller, C.; Lee, Y.; Mckinnon, P.J.; Wallace, D.; Lau, C.; Chintagumpala, M.; Ashley, D.M.; et al. Clinical, Histopathologic, and Molecular Markers of Prognosis: Toward a New Disease Risk Stratification System for Medulloblastoma. J. Clin. Oncol. 2004, 22, 984–993. [Google Scholar] [CrossRef] [Green Version]
  99. Patereli, A.; Alexiou, G.A.; Stefanaki, K.; Moschovi, M.; Doussis-Anagnostopoulou, I.; Prodromou, N.; Karentzou, O. Expression of epidermal growth factor receptor and HER-2 in pediatric embryonal brain tumors. Pediatr. Neurosurg. 2010, 46, 188–192. [Google Scholar] [CrossRef] [PubMed]
  100. Tong, C.Y.K.; Hui, A.B.Y.; Yin, X.-L.; Pang, J.C.S.; Zhu, X.-L.; Poon, W.-S.; Ng, H.-K. Detection of oncogene amplifications in medulloblastomas by comparative genomic hybridization and array-based comparative genomic hybridization. J. Neurosurg. Pediatr. 2004, 100, 187–193. [Google Scholar] [CrossRef]
  101. Ahmed, N.; Ratnayake, M.; Savoldo, B.; Perlaky, L.; Dotti, G.; Wels, W.S.; Bhattacharjee, M.B.; Gilbertson, R.J.; Shine, H.D.; Weiss, H.L.; et al. Regression of experimental medulloblastoma following transfer of HER2-specific T cells. Cancer Res. 2007, 67, 5957–5964. [Google Scholar] [CrossRef] [Green Version]
  102. Nellan, A.; Rota, C.; Majzner, R.; Lester-McCully, C.M.; Griesinger, A.M.; Mulcahy Levy, J.M.; Foreman, N.K.; Warren, K.E.; Lee, D.W. Durable regression of Medulloblastoma after regional and intravenous delivery of anti-HER2 chimeric antigen receptor T cells. J. Immunother. Cancer 2018, 6, 30. [Google Scholar] [CrossRef] [Green Version]
  103. Dai, H.-j.; Sun, B.; Yang, D.; Xu, H.; Zhu, J.; Wei, J.; Zhao, X. Eradication of medulloblastoma by NKG2D-specific CAR T-cells. J. Clin. Oncol. 2020, 38, 2522. [Google Scholar] [CrossRef]
  104. Majzner, R.G.; Theruvath, J.L.; Nellan, A.; Heitzeneder, S.; Cui, Y.; Mount, C.W.; Rietberg, S.P.; Linde, M.H.; Xu, P.; Rota, C.; et al. CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors. Clin. Cancer Res. 2019, 25, 2560–2574. [Google Scholar] [CrossRef]
  105. Donovan, L.K.; Delaidelli, A.; Joseph, S.K.; Bielamowicz, K.; Fousek, K.; Holgado, B.L.; Manno, A.; Srikanthan, D.; Gad, A.Z.; Van Ommeren, R.; et al. Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma. Nat. Med. 2020, 26, 720–731. [Google Scholar] [CrossRef]
  106. Fares, J.; Davis, Z.B.; Rechberger, J.S.; Toll, S.A.; Schwartz, J.D.; Daniels, D.J.; Miller, J.S.; Khatua, S. Advances in NK cell therapy for brain tumors. NPJ Precis. Oncol. 2023, 7, 17. [Google Scholar] [CrossRef] [PubMed]
  107. Powell, A.B.; Yadavilli, S.; Saunders, D.; Van Pelt, S.; Chorvinsky, E.; Burga, R.A.; Albihani, S.; Hanley, P.J.; Xu, Z.; Pei, Y.; et al. Medulloblastoma rendered susceptible to NK-cell attack by TGFβ neutralization. J. Transl. Med. 2019, 17, 321. [Google Scholar] [CrossRef] [PubMed]
  108. Khatua, S.; Cooper, L.J.N.; Sandberg, D.I.; Ketonen, L.; Johnson, J.M.; Rytting, M.E.; Liu, D.D.; Meador, H.; Trikha, P.; Nakkula, R.J.; et al. Phase I study of intraventricular infusions of autologous ex vivo expanded NK cells in children with recurrent medulloblastoma and ependymoma. Neuro Oncol. 2020, 22, 1214–1225. [Google Scholar] [CrossRef] [PubMed]
  109. May, K.F., Jr.; Roychowdhury, S.; Bhatt, D.; Kocak, E.; Bai, X.F.; Liu, J.Q.; Ferketich, A.K.; Martin, E.W., Jr.; Caligiuri, M.A.; Zheng, P.; et al. Anti-human CTLA-4 monoclonal antibody promotes T-cell expansion and immunity in a hu-PBL-SCID model: A new method for preclinical screening of costimulatory monoclonal antibodies. Blood 2005, 105, 1114–1120. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Lynch, T.J.; Bondarenko, I.; Luft, A.; Serwatowski, P.; Barlesi, F.; Chacko, R.; Sebastian, M.; Neal, J.; Lu, H.; Cuillerot, J.M.; et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: Results from a randomized, double-blind, multicenter phase II study. J. Clin. Oncol. 2012, 30, 2046–2054. [Google Scholar] [CrossRef]
  111. Small, E.J.; Tchekmedyian, N.S.; Rini, B.I.; Fong, L.; Lowy, I.; Allison, J.P. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin. Cancer Res. 2007, 13, 1810–1815. [Google Scholar] [CrossRef] [Green Version]
  112. Ansell, S.M.; Hurvitz, S.A.; Koenig, P.A.; LaPlant, B.R.; Kabat, B.F.; Fernando, D.; Habermann, T.M.; Inwards, D.J.; Verma, M.; Yamada, R.; et al. Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin. Cancer Res. 2009, 15, 6446–6453. [Google Scholar] [CrossRef] [Green Version]
  113. Kvistborg, P.; Philips, D.; Kelderman, S.; Hageman, L.; Ottensmeier, C.; Joseph-Pietras, D.; Welters, M.J.; van der Burg, S.; Kapiteijn, E.; Michielin, O.; et al. Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci. Transl. Med. 2014, 6, 254ra128. [Google Scholar] [CrossRef] [PubMed]
  114. Vaddepally, R.K.; Kharel, P.; Pandey, R.; Garje, R.; Chandra, A.B. Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence. Cancers 2020, 12, 738. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Friedlaender, A.; Addeo, A.; Banna, G. New emerging targets in cancer immunotherapy: The role of TIM3. ESMO Open 2019, 4, e000497. [Google Scholar] [CrossRef] [Green Version]
  116. Moon, Y.W.; Hajjar, J.; Hwu, P.; Naing, A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J. Immunother. Cancer 2015, 3, 51. [Google Scholar] [CrossRef] [Green Version]
  117. Vonderheide, R.H. CD40 Agonist Antibodies in Cancer Immunotherapy. Annu. Rev. Med. 2020, 71, 47–58. [Google Scholar] [CrossRef] [Green Version]
  118. Vermeulen, J.F.; Van Hecke, W.; Adriaansen, E.J.M.; Jansen, M.K.; Bouma, R.G.; Villacorta Hidalgo, J.; Fisch, P.; Broekhuizen, R.; Spliet, W.G.M.; Kool, M.; et al. Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma. Oncoimmunology 2018, 7, e1398877. [Google Scholar] [CrossRef]
  119. Martin, A.M.; Nirschl, C.J.; Polanczyk, M.J.; Bell, W.R.; Nirschl, T.R.; Harris-Bookman, S.; Phallen, J.; Hicks, J.; Martinez, D.; Ogurtsova, A.; et al. PD-L1 expression in medulloblastoma: An evaluation by subgroup. Oncotarget 2018, 9, 19177–19191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  120. Pham, C.D.; Flores, C.; Yang, C.; Pinheiro, E.M.; Yearley, J.H.; Sayour, E.J.; Pei, Y.; Moore, C.; McLendon, R.E.; Huang, J.; et al. Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma. Clin. Cancer Res. 2016, 22, 582–595. [Google Scholar] [CrossRef] [Green Version]
  121. Hashimoto, Y.; Penas-Prado, M.; Zhou, S.; Wei, J.; Khatua, S.; Hodges, T.R.; Sanai, N.; Xiu, J.; Gatalica, Z.; Kim, L.; et al. Rethinking medulloblastoma from a targeted therapeutics perspective. J. Neurooncol. 2018, 139, 713–720. [Google Scholar] [CrossRef] [Green Version]
  122. Sayour, E.J.; Mitchell, D.A. Immunotherapy for Pediatric Brain Tumors. Brain Sci. 2017, 7, 137. [Google Scholar] [CrossRef] [Green Version]
  123. Jähnisch, H.; Füssel, S.; Kiessling, A.; Wehner, R.; Zastrow, S.; Bachmann, M.; Rieber, E.P.; Wirth, M.P.; Schmitz, M. Dendritic cell-based immunotherapy for prostate cancer. Clin. Dev. Immunol. 2010, 2010, 517493. [Google Scholar] [CrossRef] [PubMed]
  124. Wang, S.S.; Bandopadhayay, P.; Jenkins, M.R. Towards Immunotherapy for Pediatric Brain Tumors. Trends Immunol. 2019, 40, 748–761. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Kantoff, P.W.; Higano, C.S.; Shore, N.D.; Berger, E.R.; Small, E.J.; Penson, D.F.; Redfern, C.H.; Ferrari, A.C.; Dreicer, R.; Sims, R.B.; et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 2010, 363, 411–422. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Liau, L.M.; Ashkan, K.; Tran, D.D.; Campian, J.L.; Trusheim, J.E.; Cobbs, C.S.; Heth, J.A.; Salacz, M.; Taylor, S.; D’Andre, S.D.; et al. First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J. Transl. Med. 2018, 16, 142. [Google Scholar] [CrossRef] [Green Version]
  127. Liau, L.M.; Ashkan, K.; Brem, S.; Campian, J.L.; Trusheim, J.E.; Iwamoto, F.M.; Tran, D.D.; Ansstas, G.; Cobbs, C.S.; Heth, J.A.; et al. Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination with Extension of Survival Among Patients with Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial. JAMA Oncol. 2023, 9, 112–121. [Google Scholar] [CrossRef]
  128. Ardon, H.; De Vleeschouwer, S.; Van Calenbergh, F.; Claes, L.; Kramm, C.M.; Rutkowski, S.; Wolff, J.E.; Van Gool, S.W. Adjuvant dendritic cell-based tumour vaccination for children with malignant brain tumours. Pediatr. Blood Cancer 2010, 54, 519–525. [Google Scholar] [CrossRef]
  129. McNamara, M.A.; Nair, S.K.; Holl, E.K. RNA-Based Vaccines in Cancer Immunotherapy. J. Immunol. Res. 2015, 2015, 794528. [Google Scholar] [CrossRef] [Green Version]
  130. Jahanafrooz, Z.; Baradaran, B.; Mosafer, J.; Hashemzaei, M.; Rezaei, T.; Mokhtarzadeh, A.; Hamblin, M.R. Comparison of DNA and mRNA vaccines against cancer. Drug Discov. Today 2020, 25, 552–560. [Google Scholar] [CrossRef] [PubMed]
  131. Holtkamp, S.; Kreiter, S.; Selmi, A.; Simon, P.; Koslowski, M.; Huber, C.; Türeci, O.; Sahin, U. Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells. Blood 2006, 108, 4009–4017. [Google Scholar] [CrossRef] [Green Version]
  132. Kranz, L.M.; Diken, M.; Haas, H.; Kreiter, S.; Loquai, C.; Reuter, K.C.; Meng, M.; Fritz, D.; Vascotto, F.; Hefesha, H.; et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 2016, 534, 396–401. [Google Scholar] [CrossRef]
  133. Kreiter, S.; Selmi, A.; Diken, M.; Koslowski, M.; Britten, C.M.; Huber, C.; Türeci, O.; Sahin, U. Intranodal vaccination with naked antigen-encoding RNA elicits potent prophylactic and therapeutic antitumoral immunity. Cancer Res. 2010, 70, 9031–9040. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Coban, C.; Kobiyama, K.; Aoshi, T.; Takeshita, F.; Horii, T.; Akira, S.; Ishii, K.J. Novel strategies to improve DNA vaccine immunogenicity. Curr. Gene Ther. 2011, 11, 479–484. [Google Scholar] [CrossRef]
  135. Nair, S.K.; Driscoll, T.; Boczkowski, D.; Schmittling, R.; Reynolds, R.; Johnson, L.A.; Grant, G.; Fuchs, H.; Bigner, D.D.; Sampson, J.H.; et al. Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma. J. Neurooncol. 2015, 125, 65–74. [Google Scholar] [CrossRef] [Green Version]
  136. Kaufman, H.L.; Kohlhapp, F.J.; Zloza, A. Oncolytic viruses: A new class of immunotherapy drugs. Nat. Rev. Drug Discov. 2015, 14, 642–662. [Google Scholar] [CrossRef]
  137. Aurelian, L. Oncolytic viruses as immunotherapy: Progress and remaining challenges. OncoTargets Ther. 2016, 9, 2627–2637. [Google Scholar] [CrossRef] [Green Version]
  138. Martuza, R.L.; Malick, A.; Markert, J.M.; Ruffner, K.L.; Coen, D.M. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 1991, 252, 854–856. [Google Scholar] [CrossRef]
  139. Liu, T.C.; Hwang, T.; Park, B.H.; Bell, J.; Kirn, D.H. The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma. Mol. Ther. 2008, 16, 1637–1642. [Google Scholar] [CrossRef] [PubMed]
  140. Kellish, P.; Shabashvili, D.; Rahman, M.M.; Nawab, A.; Guijarro, M.V.; Zhang, M.; Cao, C.; Moussatche, N.; Boyle, T.; Antonia, S.; et al. Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survival. J. Clin. Investig. 2019, 129, 2279–2292. [Google Scholar] [CrossRef]
  141. Stanford, M.M.; Breitbach, C.J.; Bell, J.C.; McFadden, G. Innate immunity, tumor microenvironment and oncolytic virus therapy: Friends or foes? Curr. Opin. Mol. Ther. 2008, 10, 32–37. [Google Scholar] [PubMed]
  142. Saha, D.; Martuza, R.L.; Rabkin, S.D. Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade. Cancer Cell 2017, 32, 253–267.e255. [Google Scholar] [CrossRef] [Green Version]
  143. Lang, F.F.; Conrad, C.; Gomez-Manzano, C.; Yung, W.K.A.; Sawaya, R.; Weinberg, J.S.; Prabhu, S.S.; Rao, G.; Fuller, G.N.; Aldape, K.D.; et al. Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma. J. Clin. Oncol. 2018, 36, 1419–1427. [Google Scholar] [CrossRef]
  144. Zhang, Q.; Liu, F. Advances and potential pitfalls of oncolytic viruses expressing immunomodulatory transgene therapy for malignant gliomas. Cell Death Dis. 2020, 11, 485. [Google Scholar] [CrossRef] [PubMed]
  145. Todo, T.; Ino, Y.; Ohtsu, H.; Shibahara, J.; Tanaka, M. A phase I/II study of triple-mutated oncolytic herpes virus G47∆ in patients with progressive glioblastoma. Nat. Commun. 2022, 13, 4119. [Google Scholar] [CrossRef] [PubMed]
  146. Todo, T.; Ito, H.; Ino, Y.; Ohtsu, H.; Ota, Y.; Shibahara, J.; Tanaka, M. Intratumoral oncolytic herpes virus G47∆ for residual or recurrent glioblastoma: A phase 2 trial. Nat. Med. 2022, 28, 1630–1639. [Google Scholar] [CrossRef]
  147. Lun, X.Q.; Zhou, H.; Alain, T.; Sun, B.; Wang, L.; Barrett, J.W.; Stanford, M.M.; McFadden, G.; Bell, J.; Senger, D.L.; et al. Targeting human medulloblastoma: Oncolytic virotherapy with myxoma virus is enhanced by rapamycin. Cancer Res. 2007, 67, 8818–8827. [Google Scholar] [CrossRef] [Green Version]
  148. Baryawno, N.; Rahbar, A.; Wolmer-Solberg, N.; Taher, C.; Odeberg, J.; Darabi, A.; Khan, Z.; Sveinbjörnsson, B.; FuskevÅg, O.M.; Segerström, L.; et al. Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J. Clin. Investig. 2011, 121, 4043–4055. [Google Scholar] [CrossRef] [Green Version]
  149. Lacroix, J.; Schlund, F.; Leuchs, B.; Adolph, K.; Sturm, D.; Bender, S.; Hielscher, T.; Pfister, S.M.; Witt, O.; Rommelaere, J.; et al. Oncolytic effects of parvovirus H-1 in medulloblastoma are associated with repression of master regulators of early neurogenesis. Int. J. Cancer 2014, 134, 703–716. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  150. Thompson, E.M.; Brown, M.; Dobrikova, E.; Ramaswamy, V.; Taylor, M.D.; McLendon, R.; Sanks, J.; Chandramohan, V.; Bigner, D.; Gromeier, M. Poliovirus Receptor (CD155) Expression in Pediatric Brain Tumors Mediates Oncolysis of Medulloblastoma and Pleomorphic Xanthoastrocytoma. J. Neuropathol. Exp. Neurol. 2018, 77, 696–702. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  151. Lal, S.; Carrera, D.; Phillips, J.J.; Weiss, W.A.; Raffel, C. An oncolytic measles virus-sensitive Group 3 medulloblastoma model in immune-competent mice. Neuro Oncol. 2018, 20, 1606–1615. [Google Scholar] [CrossRef] [Green Version]
  152. Studebaker, A.W.; Hutzen, B.; Pierson, C.R.; Russell, S.J.; Galanis, E.; Raffel, C. Oncolytic measles virus prolongs survival in a murine model of cerebral spinal fluid-disseminated medulloblastoma. Neuro Oncol. 2012, 14, 459–470. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Studebaker, A.W.; Hutzen, B.J.; Pierson, C.R.; Haworth, K.B.; Cripe, T.P.; Jackson, E.M.; Leonard, J.R. Oncolytic Herpes Virus rRp450 Shows Efficacy in Orthotopic Xenograft Group 3/4 Medulloblastomas and Atypical Teratoid/Rhabdoid Tumors. Mol. Ther. Oncolytics 2017, 6, 22–30. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Yu, L.; Baxter, P.A.; Zhao, X.; Liu, Z.; Wadhwa, L.; Zhang, Y.; Su, J.M.; Tan, X.; Yang, J.; Adesina, A.; et al. A single intravenous injection of oncolytic picornavirus SVV-001 eliminates medulloblastomas in primary tumor-based orthotopic xenograft mouse models. Neuro Oncol. 2011, 13, 14–27. [Google Scholar] [CrossRef] [PubMed]
  155. Friedman, G.K.; Moore, B.P.; Nan, L.; Kelly, V.M.; Etminan, T.; Langford, C.P.; Xu, H.; Han, X.; Markert, J.M.; Beierle, E.A.; et al. Pediatric medulloblastoma xenografts including molecular subgroup 3 and CD133+ and CD15+ cells are sensitive to killing by oncolytic herpes simplex viruses. Neuro Oncol. 2016, 18, 227–235. [Google Scholar] [CrossRef] [Green Version]
  156. Menyhárt, O.; Győrffy, B. Molecular stratifications, biomarker candidates and new therapeutic options in current medulloblastoma treatment approaches. Cancer Metastasis Rev. 2020, 39, 211–233. [Google Scholar] [CrossRef] [Green Version]
  157. Schuelke, M.R.; Gundelach, J.H.; Coffey, M.; West, E.; Scott, K.; Johnson, D.R.; Samson, A.; Melcher, A.; Vile, R.G.; Bram, R.J. Phase I trial of sargramostim/pelareorep therapy in pediatric patients with recurrent or refractory high-grade brain tumors. Neurooncol. Adv. 2022, 4, vdac085. [Google Scholar] [CrossRef]
  158. Hill, R.M.; Richardson, S.; Schwalbe, E.C.; Hicks, D.; Lindsey, J.C.; Crosier, S.; Rafiee, G.; Grabovska, Y.; Wharton, S.B.; Jacques, T.S.; et al. Time, pattern, and outcome of medulloblastoma relapse and their association with tumour biology at diagnosis and therapy: A multicentre cohort study. Lancet Child Adolesc. Health 2020, 4, 865–874. [Google Scholar] [CrossRef]
  159. Menyhárt, O.; Giangaspero, F.; Győrffy, B. Molecular markers and potential therapeutic targets in non-WNT/non-SHH (group 3 and group 4) medulloblastomas. J. Hematol. Oncol. 2019, 12, 29. [Google Scholar] [CrossRef] [Green Version]
  160. Taylor, L.; Wade, P.K.; Johnson, J.E.C.; Aldighieri, M.; Morlando, S.; Di Leva, G.; Kerr, I.D.; Coyle, B. Drug Resistance in Medulloblastoma Is Driven by YB-1, ABCB1 and a Seven-Gene Drug Signature. Cancers 2023, 15, 1086. [Google Scholar] [CrossRef]
  161. Gabriel, N.; Balaji, K.; Jayachandran, K.; Inkman, M.; Zhang, J.; Dahiya, S.; Goldstein, M. Loss of H3K27 Trimethylation Promotes Radiotherapy Resistance in Medulloblastoma and Induces an Actionable Vulnerability to BET Inhibition. Cancer Res. 2022, 82, 2019–2030. [Google Scholar] [CrossRef]
  162. Gareev, I.; Beylerli, O.; Liang, Y.; Xiang, H.; Liu, C.; Xu, X.; Yuan, C.; Ahmad, A.; Yang, G. The Role of MicroRNAs in Therapeutic Resistance of Malignant Primary Brain Tumors. Front. Cell Dev. Biol. 2021, 9, 740303. [Google Scholar] [CrossRef]
  163. Ge, J.; Wang, B.; Zhao, S.; Xu, J. Inhibition of lncRNA NEAT1 sensitizes medulloblastoma cells to cisplatin through modulating the miR-23a-3p-glutaminase (GLS) axis. Bioengineered 2022, 13, 7670–7682. [Google Scholar] [CrossRef]
  164. Marabitti, V.; Giansanti, M.; De Mitri, F.; Gatto, F.; Mastronuzzi, A.; Nazio, F. Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma. Front. Cell Dev. Biol. 2022, 10, 1007641. [Google Scholar] [CrossRef] [PubMed]
  165. Singh, S.K.; Hawkins, C.; Clarke, I.D.; Squire, J.A.; Bayani, J.; Hide, T.; Henkelman, R.M.; Cusimano, M.D.; Dirks, P.B. Identification of human brain tumour initiating cells. Nature 2004, 432, 396–401. [Google Scholar] [CrossRef] [PubMed]
  166. Ramaswamy, V.; Remke, M.; Bouffet, E.; Faria, C.C.; Perreault, S.; Cho, Y.-J.; Shih, D.J.; Luu, B.; Dubuc, A.M.; Northcott, P.A.; et al. Recurrence patterns across medulloblastoma subgroups: An integrated clinical and molecular analysis. Lancet Oncol. 2013, 14, 1200–1207. [Google Scholar] [CrossRef] [Green Version]
  167. Wang, X.; Dubuc, A.M.; Ramaswamy, V.; Mack, S.; Gendoo, D.M.A.; Remke, M.; Wu, X.; Garzia, L.; Luu, B.; Cavalli, F.; et al. Medulloblastoma subgroups remain stable across primary and metastatic compartments. Acta Neuropathol. 2015, 129, 449–457. [Google Scholar] [CrossRef] [Green Version]
  168. Morrissy, A.S.; Garzia, L.; Shih, D.J.H.; Zuyderduyn, S.; Huang, X.; Skowron, P.; Remke, M.; Cavalli, F.M.G.; Ramaswamy, V.; Lindsay, P.E.; et al. Divergent clonal selection dominates medulloblastoma at recurrence. Nature 2016, 529, 351–357. [Google Scholar] [CrossRef] [Green Version]
  169. Treisman, D.; Li, Y.; Zhu, Y. Stem-Like Cell Populations, p53-Pathway Activation and Mechanisms of Recurrence in Sonic Hedgehog Medulloblastoma. Neuromol. Med. 2022, 24, 13–17. [Google Scholar] [CrossRef]
  170. Raso, A.; Mascelli, S.; Biassoni, R.; Nozza, P.; Kool, M.; Pistorio, A.; Ugolotti, E.; Milanaccio, C.; Pignatelli, S.; Ferraro, M.; et al. High levels of PROM1 (CD133) transcript are a potential predictor of poor prognosis in medulloblastoma. Neuro-Oncology 2011, 13, 500–508. [Google Scholar] [CrossRef] [Green Version]
  171. Blazek, E.R.; Foutch, J.L.; Maki, G. Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia. Int. J. Radiat. Oncol. Biol. Phys. 2007, 67, 1–5. [Google Scholar] [CrossRef] [PubMed]
  172. Glumac, P.M.; Lebeau, A.M. The role of CD133 in cancer: A concise review. Clin. Transl. Med. 2018, 7, e18. [Google Scholar] [CrossRef]
  173. Zhang, L.; He, X.; Liu, X.; Zhang, F.; Huang, L.F.; Potter, A.S.; Xu, L.; Zhou, W.; Zheng, T.; Luo, Z.; et al. Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse. Cancer Cell 2019, 36, 302–318.e307. [Google Scholar] [CrossRef]
  174. Treisman, D.M.; Li, Y.; Pierce, B.R.; Li, C.; Chervenak, A.P.; Tomasek, G.J.; Lozano, G.; Zheng, X.; Kool, M.; Zhu, Y. Sox2(+) cells in Sonic Hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence. Neurooncol. Adv. 2019, 1, vdz027. [Google Scholar] [CrossRef] [PubMed]
  175. Hendrikse, L.D.; Haldipur, P.; Saulnier, O.; Millman, J.; Sjoboen, A.H.; Erickson, A.W.; Ong, W.; Gordon, V.; Coudière-Morrison, L.; Mercier, A.L.; et al. Failure of human rhombic lip differentiation underlies medulloblastoma formation. Nature 2022, 609, 1021–1028. [Google Scholar] [CrossRef]
  176. Gibson, P.; Tong, Y.; Robinson, G.; Thompson, M.C.; Currle, D.S.; Eden, C.; Kranenburg, T.A.; Hogg, T.; Poppleton, H.; Martin, J.; et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 2010, 468, 1095–1099. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  177. Wallace, V.A. Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr. Biol. 1999, 9, 445–448. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  178. Yang, Z.-J.; Ellis, T.; Markant, S.L.; Read, T.-A.; Kessler, J.D.; Bourboulas, M.; Schüller, U.; Machold, R.; Fishell, G.; Rowitch, D.H.; et al. Medulloblastoma Can Be Initiated by Deletion of Patched in Lineage-Restricted Progenitors or Stem Cells. Cancer Cell 2008, 14, 135–145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  179. Hovestadt, V.; Smith, K.S.; Bihannic, L.; Filbin, M.G.; Shaw, M.L.; Baumgartner, A.; Dewitt, J.C.; Groves, A.; Mayr, L.; Weisman, H.R.; et al. Resolving medulloblastoma cellular architecture by single-cell genomics. Nature 2019, 572, 74–79. [Google Scholar] [CrossRef] [PubMed]
  180. Vladoiu, M.C.; El-Hamamy, I.; Donovan, L.K.; Farooq, H.; Holgado, B.L.; Sundaravadanam, Y.; Ramaswamy, V.; Hendrikse, L.D.; Kumar, S.; Mack, S.C.; et al. Childhood cerebellar tumours mirror conserved fetal transcriptional programs. Nature 2019, 572, 67–73. [Google Scholar] [CrossRef]
  181. Folgiero, V.; Miele, E.; Carai, A.; Ferretti, E.; Alfano, V.; Po, A.; Bertaina, V.; Goffredo, B.M.; Benedetti, M.C.; Camassei, F.D.; et al. IDO1 involvement in mTOR pathway: A molecular mechanism of resistance to mTOR targeting in medulloblastoma. Oncotarget 2016, 7, 52900–52911. [Google Scholar] [CrossRef] [Green Version]
  182. Eckerdt, F.; Beauchamp, E.; Bell, J.; Iqbal, A.; Su, B.; Fukunaga, R.; Lulla, R.R.; Goldman, S.; Platanias, L.C. Regulatory effects of a Mnk2-eIF4E feedback loop during mTORC1 targeting of human medulloblastoma cells. Oncotarget 2014, 5, 8442–8451. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  183. Raaf, J. Relation of abnormal collections of cells in posterior medullary velum of cerebellum to origin of medulloblastoma. Arch. Neurol. Psychiatry 1944, 52, 163. [Google Scholar] [CrossRef]
  184. Rorke, L.B.; Fogelson, M.H.; Riggs, H.E. Cerebellar heterotopia in infancy. Dev. Med. Child Neurol. 1968, 10, 644–650. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Epigenetic regulation mechanisms in medulloblastoma. (A,B) CpG island methylation aberrations result in gene silencing of tumor suppressor genes and activation of oncogenes promoting oncogenesis and tumor progression. (A) CpG Island hypermethylation in tumor suppressor genes RASSF1A and HIC-1, resulting in tumorigenesis. DNMT inhibitors including decitabine and 5-azacytidine inhibit this methylation. (B) CpG Island hypomethylation in oncogene VAV1 and LIN28B downregulating a tumor suppressor gene family and promoting tumorigenesis. (C,D) Histone modifications are a form of chromatin dysregulation that results in alterations of gene functionality. HDAC inhibitors (vorinostat and fimepinostat) and EZH2 inhibitors (tazemetostat) act on these, thereby decreasing tumorigenesis. (C) Acetylation of H3K27 is upregulated in medulloblastoma, permitting transcription factors that result in tumor development and propagation. However, loss of H4K16 acetylation occurs due to decreased hMOF (a histone acetyltransferase). Hypomethylation of H3K9 and H3K4 results in unchecked oncogenes that further tumor survival. (D) Increased H3K27me3 is seen in both group 3 and group 4 medulloblastoma in a subgroup-specific manner. Abbreviations: DNMT, DNA methyltransferase; HDAC, histone deacetylase; hMOF, human males absent on the first; EZH2, enhancer of zeste homolog 2; Me, methylation; Me3, trimethylation; Ac, acetylation. Created with BioRender.com (accessed on 1 May 2023).
Figure 1. Epigenetic regulation mechanisms in medulloblastoma. (A,B) CpG island methylation aberrations result in gene silencing of tumor suppressor genes and activation of oncogenes promoting oncogenesis and tumor progression. (A) CpG Island hypermethylation in tumor suppressor genes RASSF1A and HIC-1, resulting in tumorigenesis. DNMT inhibitors including decitabine and 5-azacytidine inhibit this methylation. (B) CpG Island hypomethylation in oncogene VAV1 and LIN28B downregulating a tumor suppressor gene family and promoting tumorigenesis. (C,D) Histone modifications are a form of chromatin dysregulation that results in alterations of gene functionality. HDAC inhibitors (vorinostat and fimepinostat) and EZH2 inhibitors (tazemetostat) act on these, thereby decreasing tumorigenesis. (C) Acetylation of H3K27 is upregulated in medulloblastoma, permitting transcription factors that result in tumor development and propagation. However, loss of H4K16 acetylation occurs due to decreased hMOF (a histone acetyltransferase). Hypomethylation of H3K9 and H3K4 results in unchecked oncogenes that further tumor survival. (D) Increased H3K27me3 is seen in both group 3 and group 4 medulloblastoma in a subgroup-specific manner. Abbreviations: DNMT, DNA methyltransferase; HDAC, histone deacetylase; hMOF, human males absent on the first; EZH2, enhancer of zeste homolog 2; Me, methylation; Me3, trimethylation; Ac, acetylation. Created with BioRender.com (accessed on 1 May 2023).
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Figure 2. Main pathways of interest for targeted therapies in medulloblastoma. SHH pathway: in the absence of SHH, PTCH1 suppresses SMO activation. This suppression is released upon binding of SHH. Active SMO promotes GLI dissociation from SUFU, allowing for its translocation to the nucleus. The SMO inhibitors vismodegib and sonidegib and the CK2 inhibitor silmitasertib have been used to target this pathway. PI3K/AKT/mTOR pathway: PI3K/AKT/mTOR signaling pathway alterations play a crucial role in medulloblastoma. Several drugs that inhibit either PI3K, mTOR, or both are undergoing clinical evaluation. CDK signaling pathway: the cyclin D-CDK4/6 complex phosphorylates Rb, preventing binding of the E2F transcription factor. Translocation of E2F to the nucleus promotes S-phase entry and progression. Several clinical trials using CDK4/6 inhibitors in medulloblastoma are ongoing. Abbreviations: SHH, sonic hedgehog; SMO, smoothened; PTCH1, patched 1; SUFU, suppressor of fused homolog; GLI, glioma-associated oncogene homolog; CK2, casein kinase 2; PI3K, phosphatidylinositol-3-kinase; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; CDK, cyclin-dependent kinase; Rb, retinoblastoma. Created with BioRender.com (accessed on 1 May 2023).
Figure 2. Main pathways of interest for targeted therapies in medulloblastoma. SHH pathway: in the absence of SHH, PTCH1 suppresses SMO activation. This suppression is released upon binding of SHH. Active SMO promotes GLI dissociation from SUFU, allowing for its translocation to the nucleus. The SMO inhibitors vismodegib and sonidegib and the CK2 inhibitor silmitasertib have been used to target this pathway. PI3K/AKT/mTOR pathway: PI3K/AKT/mTOR signaling pathway alterations play a crucial role in medulloblastoma. Several drugs that inhibit either PI3K, mTOR, or both are undergoing clinical evaluation. CDK signaling pathway: the cyclin D-CDK4/6 complex phosphorylates Rb, preventing binding of the E2F transcription factor. Translocation of E2F to the nucleus promotes S-phase entry and progression. Several clinical trials using CDK4/6 inhibitors in medulloblastoma are ongoing. Abbreviations: SHH, sonic hedgehog; SMO, smoothened; PTCH1, patched 1; SUFU, suppressor of fused homolog; GLI, glioma-associated oncogene homolog; CK2, casein kinase 2; PI3K, phosphatidylinositol-3-kinase; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; CDK, cyclin-dependent kinase; Rb, retinoblastoma. Created with BioRender.com (accessed on 1 May 2023).
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Figure 3. Tumor microenvironment and immunotherapies. Adoptive cellular therapy: several strategies involving engineered immune cells, including NK cells and CAR T cells targeting different receptors overexpressed in medulloblastoma, are being evaluated preclinically or are in clinical development. Checkpoint inhibition: checkpoint inhibition is increasingly investigated in medulloblastoma patients as monotherapy or in combinatorial regimens. Along with FDA-approved PD-1/PD-L1 and CTLA-4 inhibitors that are established in other tumors, newly emerging targets including B7-H3, IDO1, and TIM-3 are being explored in preclinical and clinical settings. Tumor microenvironment: medulloblastoma generally exhibits an immunosuppressive microenvironment. It is enriched in TGF-β, inhibiting NK and CD8+ T cells and driving CD4+ T cells to Treg differentiation, which in turn release more TGF-β. Furthermore, TAMs (mainly with M2 polarization) are considered the major immune cells in the medulloblastoma microenvironment, releasing several growth factors (e.g., EGF, FGF-1, and VEGF) and expressing PD-L1 and B7-1/2, thereby inhibiting T-cell function. Abbreviations: MB, medulloblastoma; CAR, chimeric antigen receptor; NK, natural killer; AB, antibody; TAM, tumor-associated macrophage; TIL, tumor-infiltrating lymphocyte; Treg, regulatory T cell. Created with BioRender.com (accessed on 1 May 2023).
Figure 3. Tumor microenvironment and immunotherapies. Adoptive cellular therapy: several strategies involving engineered immune cells, including NK cells and CAR T cells targeting different receptors overexpressed in medulloblastoma, are being evaluated preclinically or are in clinical development. Checkpoint inhibition: checkpoint inhibition is increasingly investigated in medulloblastoma patients as monotherapy or in combinatorial regimens. Along with FDA-approved PD-1/PD-L1 and CTLA-4 inhibitors that are established in other tumors, newly emerging targets including B7-H3, IDO1, and TIM-3 are being explored in preclinical and clinical settings. Tumor microenvironment: medulloblastoma generally exhibits an immunosuppressive microenvironment. It is enriched in TGF-β, inhibiting NK and CD8+ T cells and driving CD4+ T cells to Treg differentiation, which in turn release more TGF-β. Furthermore, TAMs (mainly with M2 polarization) are considered the major immune cells in the medulloblastoma microenvironment, releasing several growth factors (e.g., EGF, FGF-1, and VEGF) and expressing PD-L1 and B7-1/2, thereby inhibiting T-cell function. Abbreviations: MB, medulloblastoma; CAR, chimeric antigen receptor; NK, natural killer; AB, antibody; TAM, tumor-associated macrophage; TIL, tumor-infiltrating lymphocyte; Treg, regulatory T cell. Created with BioRender.com (accessed on 1 May 2023).
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Table
Table 1. Clinical characteristics of the principal groups of medulloblastoma.
Table 1. Clinical characteristics of the principal groups of medulloblastoma.
WNTSHHNon-WNT/Non-SHH
Group 3Group 4
% of medulloblastoma10302535
Gender (M:F)1:11:12:13:1
Age groupChild > adultInfant, adult > childInfant, childChild > infant, adult
HistologyClassic, rarely LCADesmoplastic/nodular>
classic, MBEN, LCA		Classic, LCAClassic, LCA
ImmunoprofileB-catenin nuc (+)
YAP1/filamin A (+)
GAB1 (−)		B-catenin nuc (−)
YAP1/filamin A (+)
GAB1 (+)		B-catenin nuc (−)
YAP1/filamin A (+)
GAB1 (−)
Proposed cell of originLower rhombic lip progenitor cellsCGNPs of the EGLUndifferentiated cerebellar stem cellsUnipolar brush cells
Tumor locationFourth ventricle; infiltrating brainstemCerebellar hemispheres; rarely midlineFourth ventricle; midlineFourth ventricle; midline
Metastasis at diagnosis5–10%15–20%40–45%35–40%
Prognosis (5-year overall survival %)>95%TP53-wild type: 80%TP53 mutated (SHH-α): 40%50%75%
Abbreviations: LC/A, large cell/anaplastic; MBEN, medulloblastoma with extensive nodularity; CGNPs, cerebellar granule neuron precursors; EGL, external granule cell layer.
Table
Table 2. Molecular characteristics and targeted therapies for the principal groups of medulloblastoma.
Table 2. Molecular characteristics and targeted therapies for the principal groups of medulloblastoma.
WNTSHHNon-WNT/non-SHH
Group 3Group 4
Proposed number of subtypes2 (WNT-α and WNT-ß)4 (SHH-α, SHH-ß, SHH-γ, and SHH-δ)8 (Group 3/Group 4 subtypes I-VIII)
CytogeneticsMonosomy 6Loss of 9q, 10q, 14q, and 17p
Gain of 3q and 9p		Loss of 8q, 10q, 11q, 15q, 16q, and 17p
Gain of 1q, 7, and 18
Isochromosome: 17q		Loss of 8p, 10p, 11, and 17p Gain of 4, 7q, 17, and 18q
Isochromosome: 17q
Genomic abnormalities (most prevalent)CTNNB1, DDX3X,
SMARCA4, KMT2D,
CREBBP, CDH1, MYC, APC, ARD1A, ARID2, and TP53		PTCH1, PALB2, BRCA2, TP53, MYCN, KMT2D, SUFU, SMO, GLI2, YAP1, IDH1, and TERTMYC, GLI1B, GFI1, OTX2, DDX31, SMARCA4, PALB2, and BRCA2MYCN, CDK6, SNCAIP, KDM6A, PALB2, and BRCA2
Expression signatureWNT signalingSHH signalingMYC signature; photoreceptor/GABAergic signatureNeuronal/glutamatergic signature
Genetic targetsPARP, EGFR, WEE-1, and ALKPARP, EGFR, WEE-1, and ALKPARP, EGFR, WEE-1, and ALKPARP, EGFR, WEE-1, and ALK
Epigenetic targetsHDAC and BET/BRDSMO, HDAC, and BET/BRDHDAC, BET/BRD, and EZH2HDAC, BET/BRD, EZH2, and CDK4/6
Table
Table 3. Clinical trials involving immunotherapy in medulloblastoma.
Table 3. Clinical trials involving immunotherapy in medulloblastoma.
Therapy TypeTitleInterventionPatient AgeEnrollmentPhaseStatusTrial ID
Adoptive cellular therapyHER2-specific CAR T Cell Locoregional Immunotherapy for HER2-positive Recurrent/Refractory Pediatric CNS TumorsBiological: HER2-specific chimeric antigen receptor (CAR) T cell1 year to 26 years481RecruitingNCT03500991
EGFR806-specific CAR T Cell Locoregional Immunotherapy for EGFR-positive Recurrent or Refractory Pediatric CNS TumorsBiological: EGFR806-specific chimeric antigen receptor (CAR) T cell1 year to 26 years111Active but not recruitingNCT03638167
NKG2D-based CAR T-cells Immunotherapy for Patient With r/r NKG2DL+ Solid TumorsBiological: NKG2D-based CAR T-cells18 years to 75 years31RecruitingNCT05131763
Study of B7-H3-Specific CAR T Cell Locoregional Immunotherapy for Diffuse Intrinsic Pontine Glioma/Diffuse Midline Glioma and Recurrent or Refractory Pediatric Central Nervous System TumorsBiological: SCRI-CARB7H3(s); B7H3-specific chimeric antigen receptor (CAR) T cells1 year to 26 years901RecruitingNCT04185038
GD2-CAR T Cells for Pediatric Brain TumorsBiological: GD2-CART01 (iC9-GD2-CAR T-cells)6 months to 30 years541Not yet recruitingNCT05298995
Brain Tumor-Specific Immune Cells (IL13Ralpha2-CAR T Cells) for the Treatment of Leptomeningeal Glioblastoma, Ependymoma, or MedulloblastomaBiological: IL13Ralpha2-specific hinge-optimized 41BB-co-stimulatory CAR truncated CD19-expressing autologous T lymphocytes18 years and older301RecruitingNCT04661384
Expanded Natural Killer Cell Infusion in Treating Younger Patients with Recurrent/Refractory Brain TumorsBiological: natural killer cell therapy0 years to 21 years121CompletedNCT02271711
Immune checkpoint inhibitionImmune Checkpoint Inhibitor Nivolumab in People with Recurrent Select Rare CNS CancersDrug: nivolumab18 years to 99 years1802RecruitingNCT03173950
Pembrolizumab in Treating Younger Patients with Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or MedulloblastomaBiological: pembrolizumab1 year to 29 years1101RecruitingNCT02359565
Durvalumab in Pediatric and Adolescent PatientsDrug: durvalumab (MEDI4736)1 year to 17 years361UnknownNCT02793466
A Study to Evaluate the Safety and Efficacy of Nivolumab Monotherapy and Nivolumab in Combination with Ipilimumab in Pediatric Participants with High Grade Primary Central Nervous System (CNS) MalignanciesBiological: nivolumab
Biological: ipilimumab		6 months to 21 years1662CompletedNCT03130959
Chemo-immunotherapy Using Ibrutinib Plus Indoximod for Patients with Pediatric Brain CancerDrug: ibrutinib
Drug: indoximod
Drug: cyclophosphamide
Drug: etoposide		12 years to 25 years371RecruitingNCT05106296
Pediatric Trial of Indoximod with Chemotherapy and Radiation for Relapsed Brain Tumors or Newly Diagnosed DIPGDrug: indoximod
Radiation: partial radiation
Radiation: full-dose radiation
Drug: temozolomide
Drug: cyclophosphamide
Drug: etoposide
Drug: lomustine		3 years to 21 years1402RecruitingNCT04049669
131I-Omburtamab, in Recurrent Medulloblastoma and EpendymomaDrug: irinotecan
Drug: temozolomide
Drug: bevacizumab
Drug: omburtamab I-131
Drug: liothyronine
Drug: SSKI
Drug: dexamethasone		Up to 21 years622Active but not recruitingNCT04743661
131I-omburtamab for the Treatment of Central Nervous System/Leptomeningeal Neoplasms in Children and Young AdultsDrug: 131I-omburtamabChild, adult, and older adult522/3AvailableNCT05064306
Cancer vaccinationVaccine Immunotherapy for Recurrent Medulloblastoma and Primitive Neuroectodermal TumorBiological: TTRNA-xALT
Biological: TTRNA-DCs		Up to 30 years262Active but not recruitingNCT01326104
Decitabine/Vaccine Therapy in Relapsed/Refractory Pediatric High Grade Gliomas/Medulloblastomas/CNS PNETsBiological: vaccine (autologous dendritic cells)
Drugs: decitabine and hiltonol		2 years to 25 years11/2TerminatedNCT02332889
Vaccination With Dendritic Cells Loaded with Brain Tumor Stem Cells for Progressive Malignant Brain TumorBiological: dendritic cells
Drug: imiquimod		Child, adult, and older adult81CompletedNCT01171469
Chemotherapy and Vaccine Therapy Followed by Bone Marrow or Peripheral Stem Cell Transplantation and Interleukin-2 in Treating Patients with Recurrent or Refractory Brain CancerBiological: aldesleukin
Biological: autologous tumor cell vaccine
Biological: filgrastim
Biological: sargramostim
Biological: therapeutic autologous lymphocytes
Drug: carmustine
Drug: cisplatin
Drug: cyclophosphamide
Drug: paclitaxel		Up to 65 yearsN/A2CompletedNCT00014573
Oncolytic virotherapyPEP-CMV in Recurrent Medulloblastoma/Malignant GliomaDrug: PEP-CMV3 years to 35 years301Active but not recruitingNCT03299309
Cytomegalovirus (CMV) RNA-Pulsed Dendritic Cells for Pediatric Patients and Young Adults with WHO Grade IV Glioma, Recurrent Malignant Glioma, or Recurrent MedulloblastomaBiological: CMV-DCs with GM-CSF
Biological: Td (tetanus toxoid)		0 years to 35 years111CompletedNCT03615404
Phase 1b Study PVSRIPO for Recurrent Malignant Glioma in ChildrenBiological: polio/rhinovirus recombinant (PVSRIPO)12 years to 21 years121Active but not recruitingNCT03043391
Modified Measles Virus (MV-NIS) for Children and Young Adults with Recurrent Medulloblastoma or Recurrent ATRTBiological: modified measles virus12 months to 39 years461RecruitingNCT02962167
Wild-Type Reovirus in Combination with Sargramostim in Treating Younger Patients with High-Grade Relapsed or Refractory Brain TumorsBiological: sargramostim
Biological: Wild-type reovirus		10 years to 21 years61Active but not recruitingNCT02444546
HSV G207 in Children with Recurrent or Refractory Cerebellar Brain TumorsBiological: G2073 years to 18 years151RecruitingNCT03911388
All data concerning the clinical trials were obtained from ClinicalTrials.gov (accessed 7 April 2023).
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MDPI and ACS Style

Rechberger, J.S.; Toll, S.A.; Vanbilloen, W.J.F.; Daniels, D.J.; Khatua, S. Exploring the Molecular Complexity of Medulloblastoma: Implications for Diagnosis and Treatment. Diagnostics 2023, 13, 2398. https://doi.org/10.3390/diagnostics13142398

AMA Style

Rechberger JS, Toll SA, Vanbilloen WJF, Daniels DJ, Khatua S. Exploring the Molecular Complexity of Medulloblastoma: Implications for Diagnosis and Treatment. Diagnostics. 2023; 13(14):2398. https://doi.org/10.3390/diagnostics13142398

Chicago/Turabian Style

Rechberger, Julian S., Stephanie A. Toll, Wouter J. F. Vanbilloen, David J. Daniels, and Soumen Khatua. 2023. "Exploring the Molecular Complexity of Medulloblastoma: Implications for Diagnosis and Treatment" Diagnostics 13, no. 14: 2398. https://doi.org/10.3390/diagnostics13142398

APA Style

Rechberger, J. S., Toll, S. A., Vanbilloen, W. J. F., Daniels, D. J., & Khatua, S. (2023). Exploring the Molecular Complexity of Medulloblastoma: Implications for Diagnosis and Treatment. Diagnostics, 13(14), 2398. https://doi.org/10.3390/diagnostics13142398

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