RARE DISEASE
Medulloblastoma
Medulloblastoma
Medulloblastoma
Drug discovery
9
drugs
With orphan designations
Overview
Overview
Medulloblastoma is a malignant embryonal tumor of the cerebellum, predominantly affecting children (70% of cases) but also occurring in adults (20–40 years) [1][5][9]. It is characterized by aggressive growth and potential dissemination via cerebrospinal fluid [6]. Molecular classification (WNT, SHH, Group 3, Group 4) informs prognosis and therapy, with WNT subgroup demonstrating the best outcomes [5][17]. Standard treatment includes maximal safe resection, craniospinal radiation, and chemotherapy, tailored to risk stratification (standard vs. high-risk) [1][5][16].
Burden
Survival: 5-year OS >80% in children but lower in adults and high-risk subtypes (e.g., Group 3) [5][11][14].
Morbidity: Neurocognitive deficits, hearing/vision loss, secondary malignancies (14% at 10 years), and stroke risk [4][14].
Economic Impact: Frequent hospitalizations (HR 2.7 vs. controls) and lifelong disability supports (40% require assistance) [4][14].
Therapies
Surgery: Gross total resection prioritized, balancing oncologic control with neurological morbidity [1][6][16].
Radiation: Craniospinal irradiation (proton beam preferred for reduced toxicity) [1][16]; dose reduction in WNT subtype [13].
Chemotherapy: Platinum-based regimens (e.g., cisplatin, cyclophosphamide) for high-risk disease; subgroup-specific trials (e.g., SHH inhibitors, MEMMAT regimen for relapse) [3][8][18].
Categories: rare neoplastic diseases, rare neurological diseases
Research Papers
4,087 drug discovery papers about Medulloblastoma, with 5 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
4,087 drug discovery papers about Medulloblastoma, with 5 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-30 | Roles of cuproptosis in central nervous system tumors: from molecular mechanisms to therapeutic prospects.
Cuproptosis is a form of programmed cell death reported in 2022, characterized by copper ions directly binding to mitochondrial lipoylated proteins, inducing aberrant protein aggregation and destabilizing iron-sulfur cluster proteins, ultimately leading to cell death. Distinct from apoptosis, ferroptosis, and other known death modalities, cuproptosis does not rely on classical caspase pathways but exerts its cytotoxic effects by interfering with mitochondrial metabolism. Copper, an essential trace element for humans, maintains its homeostasis through precise regulation by transporters such as CTR1 (copper transporter 1), ATP7A (ATPase copper transporting alpha), and ATP7B (ATPase copper transporting beta). Dysregulated copper metabolism is closely associated with tumor initiation and progression. The central nervous system, being one of the organs with the highest copper content, exhibits heightened sensitivity to copper homeostasis imbalance. During metabolic reprogramming, central nervous system tumors such as glioma and medulloblastoma display enhanced copper dependency, rendering them potential targets for cuproptosis-inducing agents. However, tumor cells can develop resistance to cuproptosis through multiple mechanisms, including upregulation of ATP7A/ATP7B to promote copper efflux, downregulation of FDX1 (ferredoxin 1) and DLAT (dihydrolipoamide S-acetyltransferase) to reduce molecular sensitivity, activation of antioxidant systems such as glutathione, and metabolic switching toward glycolysis. Although several reviews have summarized cuproptosis mechanisms, a comprehensive synthesis focusing specifically on central nervous system tumors remains lacking. This review aimed to systematically examine the molecular basis of copper metabolism and cuproptosis, research progress in various central nervous system tumors, resistance mechanisms and counterstrategies, and cuproptosis-targeted therapeutic approaches. By bridging mechanistic insights with translational challenges unique to neuro-oncology, this review aimed to provide a theoretical foundation for the clinical application of cuproptosis-based therapies and to guide future research directions. Current evidence demonstrates that copper ionophores such as elesclomol and disulfiram, copper-based nanomaterials, and combination strategies with immunotherapy or radiotherapy exhibit promising antitumor efficacy in central nervous system tumor models. Meanwhile, challenges including blood-brain barrier delivery efficiency, normal neuron protection, and elucidation of resistance mechanisms remain major hurdles for clinical translation. The findings of this review could provide a theoretical foundation for the translational application of cuproptosis in neuro-oncology and guide future research directions.
2026-09-26 | The Emerging Role of Ferroptosis in Pediatric Cancer Biology and Therapy.
Ferroptosis is a regulated form of cell death caused by iron-dependent membrane lipid peroxidation. Iron metabolism, membrane lipid composition, cellular metabolic pathways, and antioxidant defense systems regulate ferroptosis. Recently, ferroptosis has attracted interest as a target in cancer therapy, in particular cancer cells have developed several biological adaptative mechanisms to evade ferroptosis, thus enhancing tumor progression, metastatic dissemination, stemness, and resistance to conventional therapies. Interestingly, ferroptosis is regulated by the tumor microenvironment, where hypoxia, immune cells, and stromal components can either stimulate or inhibit ferroptotic cell death. It has been demonstrated that targeting ferroptosis, alone or in combination with chemotherapy, radiotherapy and immunotherapy, has anticancer effects in preclinical models and may contribute to avoid treatment resistance. However, the role of ferroptosis in pediatric cancer remains incompletely understood since these kinds of tumors show different developmental, genomic, and metabolic features that may contribute to create different ferroptosis vulnerabilities. Emerging evidence in neuroblastoma, B-cell acute lymphoblastic leukemia, osteosarcoma, and medulloblastoma supports the involvement of ferroptosis-related pathways in tumor biology and treatment response. Preclinical studies also indicate that ferroptosis induction may represent a therapeutic strategy in selected pediatric cancer models, although tumor heterogeneity, drug delivery, and potential toxicity to developing tissues remain important translational challenges. This review summarizes the molecular mechanisms underlining the relationship between ferroptosis and cancer biology, tumor progression, tumor microenvironment, and therapy resistance, with particular interest in its emerging relevance and therapeutic potential in pediatric oncology, while critically considering the current evidence and major challenges for clinical translation.
2026-09-24 | Preclinical evaluation of ixazomib for high-risk pediatric brain tumors.
Many of the highest risk pediatric brain cancers continue to experience poor clinical outcomes despite intensification of current multimodal therapy. Proteasome inhibition has shown preclinical promise across a range of cancer models including diffuse midline glioma (DMG), medulloblastoma, and atypical teratoid / rhabdoid tumors (ATRT), though clinically viable agents have been limited. Recent studies in adults with glioblastoma suggest that ixazomib, a second-generation proteasome inhibitor, might achieve therapeutic concentrations in the CNS, presenting the opportunity that a CNS penetrant proteasome inhibitor might be similarly leveraged for benefit in childhood brain cancers. Ixazomib was tested against cell lines and orthotopic xenograft models of DMG, Myc-amplified medulloblastoma (Myc-MB), and ATRT. RNA sequencing and LC-MS based proteomics were utilized to define functional consequences of ixazomib treatment in these models. Proteasome activity readouts were used to assess ixazomib activity across brain regions and extracranial solid organs. Ixazomib demonstrates consistent cytotoxic effect across high-risk brain tumor models at low nanomolar concentrations. Ixazomib treatment activates proteostatic stress response and apoptosis. Treatment with ixazomib does not demonstrate survival benefit in orthotopic models, however, and pharmacodynamic testing suggests insufficient inhibition of proteasome activity within the CNS compared to extracranial tissues. While many pediatric brain tumor models demonstrate susceptibility to proteasome inhibition, ixazomib may lack sufficient blood-brain barrier penetration to be a translationally viable means of exploiting this vulnerability.
2026-09-16 | Lipidomic analysis of isolated lipid droplets reveals potential metabolic pathway differences between medulloblastoma subgroups.
Medulloblastomas (MBs) are a highly aggressive paediatric brain tumour which is very difficult to treat. Lipid metabolism has emerged as a crucial determinant of tumour progression, metastasis and therapy resistance in MBs. Lipid droplets (LDs) are lipid-rich organelles that store neutral lipids; their biology and function remain poorly characterised within MBs. MB cells from the low-aggressive Sonic hedgehog (SHH) subgroup (DAOY, UW228-2) and the high-aggressive group 3 (G4) and group 4 (G4) subgroups (D458, D283) were treated with 80 μM oleic acid (OA), 50 μM cholesterol (Chol) or a mix to induce LD formation. LDs were isolated, and lipidomic analysis was performed. No lipid species were consistently upregulated across all cell lines under any treatment condition. SHH cell lines exhibited a broad and consistent lipidomic response across all three treatments, resulting in a pronounced triacylglyceride (TAG) and cholesterol ester (CE) storage profile. The more aggressive subgroups exhibited a more selective, OA-driven phenotype, characterised by longer-chain TAG and CE species. Across all cell lines, OA produced the strongest LD expansion and metabolic separation, whereas Chol elicited a more restricted but highly subgroup-specific signature. G3/G4 Chol responses provide evidence for lipid metabolism rewiring, which could be responsible for the more aggressive phenotype. These findings demonstrate that MB subtypes not only exhibit distinct basal lipid signatures but also engage in fundamentally different lipid remodelling in response to FA overload. These distinct lipid-handling signatures display metabolic heterogeneity across MB subgroups and suggest subtype-specific vulnerabilities. Overall, these findings position LD remodelling as a potential metabolic target of MB cells.
2026-09-09 | Suppression of medulloblastoma by TLR9 activation
Medulloblastoma is an embryonal tumor of the cerebellum that primarily affects children. In recent years, progress has been made in understanding the pathological, genetic, and molecular heterogeneity of medulloblastoma; however, as solid tumors grow in an extraordinarily complex microenvironment, further research into risk classification, prognosis, and treatment is needed. Multiple factors related to tumor pathophysiology, including the immune system, influence tumor growth and the response to chemotherapy. Toll-like receptor agonists have been used, alone or in combination with conventional treatments, to increase tumor chemosensitivity and prolong survival in cancer patients. However, these aspects remain unexplored in the context of medulloblastoma. The present study aimed to determine the effects of administering the synthetic TLR7 and TLR9 agonists on the development of SHH medulloblastoma. We administered the synthetic oligonucleotide (ODN1826) or resiquimod (R848) intratumorally into established subcutaneous xenografts in immunodeficient nu/nu mice and examined their effects on tumor volume and the expression of markers associated with proliferation, apoptotic cell death, and vascularization. Our results showed that treatment with ODN1826 resulted in a significant reduction in tumor volume, accompanied by decreased Ki67 and CD31 expression in tumor tissue, whereas cleaved caspase-3 expression showed a slight, non-significant increase. These findings support further investigation of TLR9 activation as a potential therapeutic strategy for medulloblastoma.
cell therapies
2026-09-29 | Next-generation CAR-T therapy for malignant brain tumors: latest updates from the 2026 AACR Annual Meeting.
The 2026 AACR Annual Meeting showcased rapid progress in chimeric antigen receptor (CAR) T-cell therapy for malignant brain tumors. This correspondence synthesizes 12 clinical and translational abstracts addressing early efficacy, resistance mechanisms, target discovery, and next-generation engineering. Phase I studies in glioblastoma demonstrated feasibility, manageable toxicity, cellular persistence, and preliminary radiographic activity, while revealing antigen loss and treatment-associated myeloid suppression. Longitudinal and spatial analyses further identified limited CAR T-cell persistence, anti-CAR immune responses, and remodeling of suppressive tumor niches. Preclinical strategies sought to overcome these barriers through programmable antigen recognition, alternative KIR/DAP12 signaling, stress-granule modulation, inducible metabolic support, membrane-tethered cytokine agonists, resistance to transforming growth factor beta, and dual targeting of tumor cells and immunosuppressive macrophages. Surfaceome profiling and affinity-guided receptor optimization also identified promising targets in glioblastoma and medulloblastoma. Collectively, these findings support mechanism-informed CAR T-cell platforms, while emphasizing that durability, neurotoxicity, trafficking, immunogenicity, and patient selection require validation in larger clinical studies.
2026-08-08 | CAR T-cell therapy in pediatric brain tumors: a narrative review with comparative analysis of clinical trial eligibility criteria.
Pediatric brain tumors are the leading cause of cancer-related mortality in children, and current standard therapies like surgery, radiotherapy, and chemotherapy offer limited survival benefits and significant long-term morbidity. Chimeric antigen receptor (CAR) T-cell therapy is a transformative treatment for hematologic malignancies and is now being explored for pediatric brain tumors. This review summarizes the latest advances, preclinical and clinical findings, challenges of CAR T-cell therapy, and future directions in pediatric neuro-oncology. 18 studies that met the eligibility criteria were selected, consisting of preclinical models, early-phase clinical trials, and translational studies. A registry search of central nervous system (CNS) tumor trials from Clinicaltrials.gov, ISRCTN, and ANZCTR identified 12 active or completed interventional trials of CAR T-cell therapy in patients with CNS tumors, their eligibility criteria and parameters were compared. Preclinical studies consistently demonstrate that CAR T-cells targeting antigens such as B7-H3, GD2, HER2, IL13Rα2, and EphA2 can induce robust and specific tumor regression in models of medulloblastoma, diffuse intrinsic pontine glioma (DIPG), ependymoma, and high-grade gliomas. On the other hand, B7-H3 is a pan-pediatric target due to its high expression in multiple CNS tumors, including medulloblastoma, ependymoma, and glioma, whereas GD2 is highly relevant for H3K27M-mutant diffuse midline gliomas. Early-phase clinical trials confirm that CAR T-cells can traffic to CNS tumors, infiltrate tumor tissue, and mediate tumor regression. The ICV B7-H3 phase 1 trial in DIPG achieved noteworthy results, with a median survival of 19.8 months across 21 patients and 3 patients surviving more than 40 months. GD2-CAR T-cell therapy in H3K27 M-mutant gliomas showed partial clinical responses, with neurotoxicity and encephalopathy observed, whereas the HER2-targeted locoregional therapy showed no dose-limiting toxicities. Future interventions such as multi-antigen targeting, combinatorial CAR designs, and enhanced cytokine signaling are being developed to improve efficacy and safety. A comparison of 12 registered pediatric CAR T-cell trials showed heterogeneity in eligibility criteria, including age ranges, performance status thresholds, H3K27M mutation requirements, and geographic concentration bias. CAR T-cell therapy holds significant promise for improving outcomes in pediatric brain tumors, but its clinical translation is challenged by tumor heterogeneity, antigen escape, neurotoxicity, and the immunosuppressive tumor microenvironment.
2026-08-07 | Locoregional and systemic adoptive cellular therapies for pediatric brain tumors: a systematic review of CAR‑T, TCR‑engineered T cells, and NK cell strategies.
Adoptive cellular therapies may expand treatment options for pediatric brain tumors by focusing activity on tumor antigens and limiting off-tumor effects. We systematically reviewed preclinical and clinical evidence for CAR T cells, TCR-engineered T cells, and NK or γδ T-cell platforms directed against HER2, B7-H3 (CD276), EGFR806-reactive EGFR, GD2, IL13Rα2, and EphA2 or EphA3, with attention to delivery route, safety, persistence, and combination strategies. Following PRISMA, we searched PubMed, Embase, and Scopus from inception through September 17, 2025, restricted to English. The search yielded 324 records; 103 duplicates were removed; 221 titles and abstracts were screened; 180 full texts were reviewed; and 34 studies were extracted by two independent reviewers. We captured design, tumor and molecular features, product engineering, route and schedule, lymphodepletion, toxicities including cytokine release syndrome, immune effector cell associated neurotoxicity, and tumor inflammation associated neurotoxicity, radiographic or clinical response, survival, and correlatives such as persistence or trafficking in blood, cerebrospinal fluid, or tumor tissue, cytokines, and antigen dynamics. In vivo studies showed reproducible antitumor activity for HER2 in medulloblastoma, GD2 in diffuse midline glioma, and multi-antigen constructs incorporating IL13Rα2 and EphA2 in medulloblastoma and ependymoma, with significant survival advantages compared with controls. γδ T cells targeting the EphA axis selectively killed medulloblastoma with neural sparing; GD2 CAR NK-92 inhibited diffuse intrinsic pontine glioma growth. In early clinical programs, route shaped safety and pharmacodynamics. For GD2, low-dose intravenous induction followed by repeated intraventricular dosing produced objective radiographic regressions and manageable tumor inflammation associated neurotoxicity, while dose-limiting cytokine release syndrome was confined to higher intravenous doses. Intraventricular B7-H3 CAR T cells, given without lymphodepletion, enabled multi-cycle dosing with mainly grade 1 to 2 events and cerebrospinal fluid localized persistence. Weekly intracranial EGFR806 CAR T cells were feasible and well tolerated, with stable disease as the best response in a small cohort. Across trials, persistence and immune activation were most evident in cerebrospinal fluid, supporting cerebrospinal fluid centered pharmacodynamic monitoring. Mechanism-based combinations, including IGF-axis inhibition in diffuse midline glioma and epigenetic priming of GD2 with an integrated safety switch in medulloblastoma, enhanced activity. The evidence supports pediatric-centric antigen selection and a CNS-first, locoregional dosing approach to increase on-tumor exposure and reduce systemic toxicity. Priorities include multi-antigen strategies to prevent escape, incorporation of safety switches, earlier deployment when tumor burden is low, and prospective cerebrospinal fluid pharmacodynamics in multisite phase II studies.
2026-07-27 | Intracerebroventricular B7-H3-targeting CAR T cells for non-pontine DMG and recurrent/refractory pediatric CNS tumors: a phase 1 trial.
High-grade central nervous system (CNS) tumors carry a poor prognosis with limited curative options if first-line therapy fails. B7-H3 is expressed in many of these tumors, and chimeric antigen receptor (CAR) T cell therapy is an emerging immunotherapeutic strategy. BrainChild-03 (NCT04185038) is a single-center, dose-escalation phase 1 study of repeated intracerebroventricular (ICV) B7-H3 CAR T cells in children and young adults with recurrent/refractory CNS tumors (Arms A, B) and diffuse intrinsic pontine glioma (DIPG, Arm C). Here, we report results from Arm B, in which patients with refractory/relapsed CNS tumors or pre- or post-progression non-pontine diffuse midline glioma (DMG) received repeated ICV infusions. Primary objectives were feasibility and safety/tolerability; secondary objectives included CAR T cell detection, disease response, and survival. Of 36 enrolled patients (atypical teratoid rhabdoid tumor n = 5, DMG n = 8, embryonal tumor with multilayer rosettes n = 2, ependymoma n = 4, high-grade glioma n = 6, medulloblastoma n = 8, pineoblastoma n = 3), manufacturing was successful for 35 patients, 26 of whom received therapy. Median age was 10 years (range 1-26). Dose escalation from 1 × 107 to 10 × 107 CAR T cells/dose identified this dose as the maximally tolerated dose regimen, with no dose-limiting toxicities observed. Across 181 total doses (median 7/patient), common adverse events included headache (n = 26), fever (n = 15), and nausea (n = 14). Median survival from first infusion was 11.5 months, ranging from 3.2 months (pineoblastoma, HGG) to 21.4 months (ependymoma); two patients achieved a partial response. Repeated ICV B7-H3 CAR T cell dosing is feasible and tolerable across a spectrum of pediatric CNS tumors, supporting continued investigation in future trials.
2026-06-04 | Tumor Microenvironmental Regulation of CAR T-Cell Therapy in High Risk Medulloblastoma.
B7-H3-directed chimeric antigen receptor (CAR) T cell therapy has demonstrated clinical safety and antitumor activity in pediatric brain tumors (pBTs) but lacks durable responses. Although preclinical studies show efficacy, the CAR designs that best support sustained function in immunosuppressive tumor microenvironments (TMEs) remain unclear. Group 3 medulloblastoma (G3MB) is a lethal pBT with poor responsiveness to immunotherapy. Within the TME, myeloid cells dominate the immune landscape and regulate T cell function through innate immune pathways, including the Toll-like receptor 7/8 (TLR7/8) axis. While TLR7/8 agonists activate antitumor myeloid programs, their integration with CAR T-cell therapy has not been explored. Therefore, we hypothesize that CAR architecture and TLR7/8-mediated myeloid activation cooperatively govern CAR T-cell function and subsequent therapeutic outcomes in G3MB. B7-H3 CARs incorporating CD28, 4-1BB, or dual CD28/4-1BB co-stimulation were evaluated in vitro and in orthotopic G3MB models. Resiquimod was formulated in a brain-penetrant poly (2-oxazoline) nanoparticle (ResiPOx) to activate TLR7/8-expressing myeloid cells. T cell and myeloid states were assessed by flow cytometry, bulk, and single-cell RNA sequencing. CAR designs showed similar tumor control in immunodeficient hosts but diverged in immunocompetent models, where dual-costimulatory CAR T-cells demonstrated superior cytotoxicity and persistence. The optimal CAR induced sustained CAR T-cell cycling and TAM reprogramming while downregulating TLR7/8 in dominant myeloid clusters. ResiPOx enhanced CAR T-cell efficacy by activating myeloid cells and reducing suppressive populations. Optimized CAR design combined with TLR7/8-mediated myeloid reprogramming enhances T cell activity, supporting TME-guided immunotherapy for G3MB.
proteins
2026-09-14 | Local delivery of interferon restores antigen presentation and sensitizes medulloblastoma to T cell killing.
Medulloblastomas are considered immunologically cold and refractory to immunotherapy. One factor contributing to their low immunogenicity is impaired antigen presentation, which allows tumor cells to evade cytotoxic T cells. Using a syngeneic mouse model of medulloblastoma, we demonstrate that despite low expression of MHC class I on tumor cells, depletion of CD8+ T cells accelerates tumor growth, whereas adoptive transfer of tumor-reactive CD8+ T cells prolongs survival. These antitumor effects rely on T cell-derived interferon gamma (IFNγ), which induces MHC class I on tumor cells and facilitates tumor cell killing by T cells. Importantly, delivering IFNγ directly into tumors via convection-enhanced delivery enhances CD8+ T cell-mediated killing of tumor cells and significantly prolongs survival in tumor-bearing mice. These studies highlight the importance of T cells in controlling brain tumors and the value of IFNγ as an adjuvant for T cell-based immunotherapy.
2026-07-10 | Ang2 and TAT targeting of leptomeningeal disease by the intravenous and intrathecal routes: a comparative analysis.
Leptomeningeal disease (LD), involving the metastasis of cells to the leptomeningeal membranes in the central nervous system (CNS), can be a deadly complication of several different types of cancer originating in the periphery or CNS, including breast cancer (BC) and pediatric medulloblastoma (MB). Targeted therapy represents a promising new approach to improve overall survival for LD patients. To this date, angiopep-2 (Ang2) and transactivating transcriptional activator (TAT), two well-known peptides for their brain delivery capability, have been reported to transport therapeutic cargos into the CNS for treatment of disease. Current administration strategies, however, still rely on oral delivery or intravenous injection (IV), where the substances need to travel through complex biological barriers to reach the subarachnoid space (SAS), which is the primary location of LD. Our research group has focused on the intrathecal (IT) route of administration as an alternative approach that can potentially enable high exposure of drug to CSF exposed tissues. However, there is a major field gap in understanding how targeting peptides can access (or not access) LD as a function of their route of administration. Therefore, our work was focused on comparing the targeting capability of Ang2 vs TAT by IT vs IV routes of administration. We first generated two xenograft models of LD by directly infusing breast cancer cells (MDA-MB231) or medulloblastoma cells (HDMB03) into the SAS via intracisternal magna injection (ICM) to form BC-LD and MB-LD models, respectively. These tumor models were characterized for overall survival, tumor growth patterns, and presence of hydrocephalus. Second, we further administered fluorescently labeled Ang2 or TAT peptides either IV or ICM into tumor bearing mice. Neuraxial fluorescence images were examined to evaluate the targeting ability of these two peptides based on colocalization between peptide signal and tumor tissues ex vivo . We discovered that the median survival of both models was negatively related to the number of the cells infused. While HDMB03 cells tended to metastasize preferentially to the brain region, MDA-MB231 cells tended to metastasize preferentially to the spinal cord. Both models present hydrocephalus as one of the common clinical symptoms in LD patients. Compared to the healthy control, MB-LD yielded a 7.3-fold increase and BC-LD a 26.5-fold increase in ventricular volume. Furthermore, targeting achieved by TAT was significantly higher than targeting achieved by Ang2 in thoracic spine for the MB-LD model. For BC-LD model, TAT's signal was found significantly higher than Ang2's signal in olfactory bulbs, brain stem, thoracic spine, and lumbar spine regions. While both peptides showed a strong signal at 2 hours post ICM injection, signal was not detectable 24 hours after administration, reflecting washout or degradation. Significantly, these data provide evidence that ICM will be a preferable route of administration over IV for the purpose of maximally targeting LD.
2026-05-13 | Growth Outcomes and Relapse Risk in Pediatric Medulloblastoma Survivors with and Without Growth Hormone Therapy: A 23-Year Single-Center Cohort Study.
Background: Growth hormone deficiency (GHD) is one of the most common endocrine sequelae in survivors of pediatric medulloblastoma, largely resulting from hypothalamic-pituitary irradiation. Concerns regarding the oncologic safety of growth hormone (GH) replacement have historically limited its use. This study aimed to evaluate growth response to GH therapy and its potential association with tumor relapse in medulloblastoma survivors treated between 2000 and 2023. Methods: We conducted a retrospective single-center cohort study including 74 patients diagnosed with medulloblastoma before 18 years of age. GHD was confirmed by stimulation testing according to standard criteria. Auxological, endocrine, and oncologic data were collected longitudinally. Growth outcomes were compared among patients without GHD (n = 38), patients with untreated GHD (n = 13), and patients with GHD receiving GH treatment (n = 23). Relapse rates were assessed following GH initiation and compared with those of untreated patients. Results: GHD was diagnosed in 48.7% of patients. Baseline height SDS did not differ among groups. Patients with untreated GHD experienced a significant decline in height SDS (-1.93 ± 0.78), whereas GH-treated patients showed a significant increase (+0.39 ± 0.06; p < 0.0001). Final height SDS was significantly lower in untreated GHD patients (-2.45 ± 0.36) compared with GH-treated patients (-1.71 ± 0.68) and patients without GHD (-0.68 ± 0.24; p < 0.0001). No evidence of an increased risk of tumor relapse was observed in association with GH therapy during follow-up. Conclusions: GH replacement significantly improves growth outcomes in medulloblastoma survivors with confirmed GHD without apparent increase in relapse risk when initiated after stable remission. The early identification and multidisciplinary management of GHD are essential components of long-term survivorship care.
2026-05-04 | PC3/Tis21/BTG2 and BTG1 genes: regulators of the cell cycle and neurogenesis, as well as tumor suppressors in malignant brain tumors.
PC3/Tis21/BTG2 and BTG1, prototype members of the BTG/Tob family, are antiproliferative transcriptional cofactors discovered 35 years ago as genes induced by nerve growth factor and phorbol 12-myristate 13-acetate or associated with lymphocytic leukemia. They are today known to serve as developmental regulators in several tissues, including neural cells. Biological functions such as cell division, transcriptional control, DNA repair, and mRNA stability, have been linked to their protein products. We will focus in this review on the effects of PC3/Tis21/BTG2 and BTG1 on brain tumorigenesis and neural development, and on cell cycle and apoptosis. In fact, these genes act as tumor suppressors, and their ability to control tumorigenesis in medulloblastoma and glioma is intrinsically linked to their ability to control the differentiation and proliferation of neural stem and progenitor cells during neurogenesis. Chief function of PC3/Tis21/BTG2 during pre/postnatal and adult neurogenesis is its requirement for the differentiation and migration of neural progenitor cells, in adult hippocampus and subventricular zone-which are the main neurogenic niches where adult neurogenesis occurs-as well as in postnatal cerebellum. Moreover, PC3/Tis21/BTG2 inhibits medulloblastoma onset by promoting the migration and differentiation of cerebellar precursor cells outside the external granular layer, i.e., the proliferative epithelium of the cerebellum, thus diminishing their susceptibility to oncogenic transformation under the influence of Sonic Hedgehog. BTG1, by contrast, primarily functions in neurogenesis to inhibit the proliferation of neural stem and progenitor cells, thereby ensuring the preservation of the cell pool and maintaining the quiescence of medulloblastoma cancer stem cells-known for their persistence against treatments and involvement in tumor relapses-thus preventing their entry in cycle. Furthermore, in glioma, PC3/Tis21/BTG2 enhances apoptosis rates while simultaneously decreasing the migration and invasion of cancerous cells, and lowering the levels of cyclin D1. Similarly, BTG1 contributes to the growth arrest of glioma cells through the regulation of cyclin D1 and p21 expression. PC3/Tis21/BTG2 and BTG1 bind and regulate multiple genes, including Id3, cyclin D1, PRMT1 and the chemokine Cxcl3. These interactions underscore the potential of these cofactors in controlling neurogenesis and tumorigenesis through multiple molecular pathways.
2025-06-01 | COG133 peptide-conjugated lipid nanoparticles sensitize medulloblastoma to radiation therapy in mice.
Medulloblastoma (MB) is a malignant brain tumor that often arises in the cerebellum and has a propensity for spreading to the spinal cord or other parts of the central nervous system (CNS). Craniospinal irradiation (CSI) has long been a cornerstone in the treatment of MB, especially for patients with high-risk or metastatic disease. However, CSI often leads to long-term neurocognitive deficits, including learning disabilities, and growth abnormalities, especially in children. In this study, we aimed to decrease the dose of irradiation and the proliferation of MB by using Volasertib (VSB), a Polo-like kinase 1 (PLK1) specific inhibitor. VSB was highly potent in-vitro with an IC50 of 27.43 nM and 13 nM in HDMB03 and DAOY cells, respectively. However, in the orthotopic MB mouse model, VSB as a free drug did not improve overall survival or decrease tumor burden. Hence, we encapsulated VSB in COG133-conjugated lipid nanoparticles (COG133-LNPs) to circumvent the blood-brain barrier (BBB). We observed that COG-133-LNPs loaded with VSB increased the biodistribution of VSB by three folds than the non-targeted LNPs in the brain. Furthermore, COG133-LNPs along with irradiation decreased tumor burden significantly as compared to VSB or radiation alone. To our observation, COG133-LNPs display high potency in killing MB cells and sensitizing them toward radiation therapy.
oligonucleotides
2026-06-03 | Exploration of miR-326 delivery via biocompatible polymeric nanoparticles in medulloblastoma: A preliminary study.
MicroRNAs play a crucial role in tumorigenesis, functioning as oncogenes or tumor-suppressors while orchestrating the differentiation states of cancer cells. In medulloblastoma, the most common malignant pediatric brain tumor, the downregulation of miR-326 is associated with a loss of tumor suppression that leads to uncontrolled proliferation and survival or de-differentiation. In this study, we explore an innovative approach for microRNA delivery using polycaprolactone/chitosan-based nanoparticles. We evaluate the biocompatibility of the nanocarrier in medulloblastoma cell lines and report results on in vivo nanoparticles administration, demonstrating minimal toxicity in the most exposed organs. In vitro findings reveal that nanoparticles-mediated miR-326 delivery significantly reduces stemness markers (Nanog and Sox2) and promotes neuronal differentiation, as evidenced by increased β3-tubulin expression. These results highlight polycaprolactone-based nanoparticles as a promising platform for miR-326 delivery, establishing a foundation for future investigations on therapeutic strategies in medulloblastoma.
2025-11-07 | The MYC-dependent lncRNA MB3 inhibits apoptosis in Group 3 Medulloblastoma by regulating the TGF-β pathway via HMGN5.
Group 3 (G3) is one of the most common and aggressive subtypes of the paediatric cerebellar tumour Medulloblastoma (MB), primarily driven by the MYC oncogene. The challenging targeting of MYC, coupled with gaps in understanding G3 MB molecular bases, has hindered the development of targeted therapies. The unconventional oncogenic roles of long noncoding RNAs (lncRNAs) offer opportunities to address this complexity, to provide insights and to identify novel targets. Using -omics approaches and molecular/cellular assays, we elucidate the mode-of-action of lncMB3, a MYC-dependent, anti-apoptotic lncRNA in G3 MB. LncMB3 regulates the TGF-β pathway, critically altered in G3 medulloblastomagenesis, via direct binding and translational inhibition of the mRNA for the epigenetic factor HMGN5. This regulatory axis affects apoptosis through photoreceptor lineage genes, including the G3 driver OTX2. The synergistic effects between lncMB3 targeting and cisplatin treatment underscore the relevance of this network. Additionally, we propose novel ferritin-based nanocarriers for the efficient delivery of antisense oligonucleotides against lncMB3. LncMB3 crucially links MYC amplification and apoptosis inhibition through a circuit involving RNA-based mechanisms, G3 MB key determinants and underexplored factors. This integrated framework deepens the understanding of G3 MB landscape and supports the potential for translating lncRNA research into future applications.
2025-06-24 | Delivery of LOXL1-AS1-siRNAs using targeting peptide-engineered extracellular vesicles with focused ultrasound to suppress medulloblastoma metastasis.
Metastasis of medulloblastomas (MBs) is difficult to treat and remains the primary cause of death in children with this brain tumor. Current treatment focuses on radiotherapy to limit metastatic recurrence and maintain survival, but this may cause long-term neurocognitive deficits. This challenge emphasizes the need for novel targeted therapies to combat metastatic MB. In this study, we report an RNA therapy model using targeted extracellular vesicles (EVs) to deliver therapeutic small-interfering (si)RNAs to MB. First, MB-targeted EVs (MB-tEVs) were generated via genetic modification of EV-producing cells to express E1-3, an MB-specific peptide. Next, isolated MB-tEVs were loaded with siRNAs that targeted LOXL1-AS1, a pro-metastatic long non-coding RNA in sonic-hedgehog MB (SHH-MB). Expression of the E1-3 peptide increased MB-tEV internalization into MB cells, where the delivered siRNAs effectively silenced LOXL1-AS1 and suppressed LOXL1-AS1-mediated metastatic traits of SHH-MB cells in vitro. Locoregional application of microbubble-enhanced focused ultrasound (FUS) improved the accumulation of systemically injected EVs in the mouse brain. Mice treated with siRNA-loaded MB-tEVs had decreased LOXL1-AS1 expression, reduced metastases, and improved survival in an SHH-MB orthotopic model. Our study provides the first and very promising evidence for the combined use of tumor-targeted EVs and microbubble-enhanced FUS to deliver therapeutic siRNAs to suppress metastatic MB, potentially supporting conventional treatments and improving clinical outcomes of this malignant pediatric tumor.
2025-02-06 | Integrated interactome, proteomic and functional analyses reveal molecular pathways driving L1TD1-induced aggressiveness in CNS embryonal tumor cells.
L1TD1 is a pluripotency factor required for embryonic stem cell self-renewal; its expression has also been detected in solid tumors, including embryonal tumors of the central nervous system (CNS). Previously, we showed that L1TD1 expression correlates with metastasis formation and shorter overall survival of medulloblastoma patients. Here, we used affinity purification coupled to mass spectrometry to map the L1TD1 interactome, and global proteomics to assess proteins differentially regulated by L1TD1 expression in patient-derived embryonal CNS tumor cell lines. We identified novel L1TD1 interactors and differentially expressed proteins related to cell proliferation, death and motility. Finally, we demonstrated that L1TD1-overexpressing tumor cells have distinct cell morphology with enhanced filopodial formation, higher cell motility, greater proliferation capability, and reduced sensitivity to cisplatin treatment.
2025-01-06 | Tumor Suppressor microRNAs as Potential Treatment Therapeutics for Advanced Medulloblastoma
Medulloblastoma (MB) is one of the most prevalent forms of malignant brain cancer observed within pediatric patients and is particularly difficult to diagnose and treat due to the anatomical localization of tumors near the brainstem. Currently, there are four molecular classifications of MBL: WNT, SHH, Group 3, and Group 4 tumor subgroups. Wingless-type (WNT) mutant tumors are the least common, often caused by mutations in the CTNNB1 gene that plays a crucial role in the wingless cell signaling pathway, yet associates with the best prognosis as compared to all other MBL subtypes. Sonic hedgehog (SHH) mutant tumors arise due to continued release of Shh from purkinje cells, and an uninhibited proliferation response by granular neuronal precursors (GNPs). Group 3 and 4 MBL subgroups are still a molecularly heterogeneous class of tumors, with Group 3 MBL being highly associated with metastasis upon diagnosis, and more prevalently characterized by MYC amplification and activation. Group 4 MBL tumors comprise approximately 40% of all MBL, and remain remarkably heterogeneous with respect to somatic mutations of genes such as KDM6A, OTX2, ZMYM3, with an approximate 80% of tumors harboring chromosome 17 copy number alterations. While a majority of MBL cases cannot be linked to a single protein coding gene alteration, the role of non-coding RNAs, such as miRNAs, seems quite promising as a genetic marker to further sub-categorize MBL at the molecular level. Furthermore, miRNA-based therapy is proving to be a promising treatment to curb the growth of a number of cancer types within the clinic, with particular miRNAs under investigation including miR-34a, miR-211, and miR-584-5p. These miRNAs are known to induce cell cycle arrest in mouse models and demonstrate anti-tumorigenic properties in vitro, meriting further investigation of miRNA-based clinical trials for pediatric MBL patients.
other
2026-09-25 | Divergent medulloblastoma chromatin states disclose KDM2B as a selective dependency.
Medulloblastoma is a biologically heterogeneous childhood cerebellar tumor harboring frequent chromatin-modifying gene alterations. How these alterations promote transcriptional programs governing malignancy remains poorly defined. To address this knowledge gap, we evaluated chromatin states across medulloblastoma subgroups by multi-modal integration of histone modifications with mutational, DNA methylation and transcriptomic profiles. A bivalent/poised enhancer (EnhBiv) state was specifically enriched at the promoters of neurodevelopmental genes in Group 3/4 medulloblastoma. Integrative bioinformatics coupled with chromatin occupancy studies identified aberrant KDM2B binding at EnhBiv-enriched promoters. CRISPR-mediated knockout or acute protein degradation of KDM2B selectively suppressed the growth of medulloblastoma models in vitro and in vivo. Mechanistically, KDM2B promotes sequential recruitment of Polycomb repressive complexes (PRC1/PRC2) and EnhBiv chromatin, thereby repressing neuronal differentiation programs. Collectively, we provide foundational insights into an epigenetic basis of medulloblastoma, nominating KDM2B as a selective dependency in high-risk subgroups that warrants consideration as a candidate therapeutic target.
2026-09-23 | Spatial and single-cell dissection of medulloblastoma identifies developmental hierarchies and a prognostic PPIA-BSG tumor-immune axis.
Medulloblastoma (MB) in children is highly heterogeneous, leading to its classification into molecular subgroups and resulting in significant differences in clinical outcomes even within the same risk group. This heterogeneity severely hampers the clinical management of MB. Therefore, it is essential to characterize MB heterogeneity within its tumor microenvironment. Deep single-cell RNA sequencing (scRNA-seq) was performed on tumor tissues and matched adjacent normal tissues from two WNT, three Group 4 (G4), and one Sonic Hedgehog (SHH) MB patients. In addition, tumor tissue and adjacent cerebellar tissue from one patient in each subgroup were subjected to matched spatial transcriptomic sequencing. A total of 316,446 single cells from MB and adjacent tissues were profiled by scRNA-seq. The cellular characteristics and developmental trajectories of granule cell precursors, unipolar brush cells, neural stem cells, microglia, and immune populations were defined, along with transcriptomic features associated with candidate cells of origin in MB. Infiltrating immune cells were present within tumors and exhibited an activated regulatory T-cell phenotype. Cell-cell communication analysis identified the PPIA-BSG co-receptor as a critical signaling axis in MB. Multiplex immunofluorescence and external bulk transcriptomic validation identified PPIA-BSG co-receptor as an independent prognostic factor. Single-cell transcriptomic analysis delineates the cellular ecosystem of tumor and adjacent tissue-derived populations in MB, with particular emphasis on candidate cells of origin across molecular subgroups. These findings suggest that infiltrating immune cells may provide a foundation for immunotherapeutic strategies in MB and identify PPIA-BSG co-receptor as a potential therapeutic target.
2026-09-15 | PSEN1 Expression Identifies a Developmentally Distinct Favourable-Prognosis State in SHH α Medulloblastoma.
Although PSEN1 is best known for its role in Alzheimer's disease, it also regulates neural development and cerebellar morphogenesis. Medulloblastoma (MB) is the most common malignant paediatric brain tumour and arises from disrupted cerebellar developmental programmes. The clinical significance of PSEN1 in MB remains unknown. We investigated the prognostic value and transcriptional correlates of PSEN1 expression across molecular subgroups and subtypes of MB. Public bulk and single-cell transcriptomic datasets were used to examine PSEN1 expression, associations with overall survival (OS) and transcriptional correlates in MB. The SHH α-associated transcriptional pattern was evaluated in an independent cohort, and PSEN1 expression was further examined in the developing human cerebellum and across paediatric brain tumour types. Genes strongly correlated with PSEN1 in SHH α MB were subjected to gene ontology (GO) enrichment analysis. High PSEN1 expression was consistently associated with significantly longer OS exclusively in SHH α MB. The PSEN1-associated transcriptional pattern was reproduced in an independent SHH α cohort. PSEN1 was expressed across developing cerebellar cell populations and paediatric brain tumour types, with MB showing intermediate expression among the tumour entities examined. In SHH α MB, PSEN1 was associated with a coordinated transcriptional programme enriched for RNA homeostasis, intracellular membrane trafficking, protein quality control, lipid and calcium signalling and developmental pathways. High PSEN1 expression identifies a favourable-prognosis subset of SHH α MB and is associated with a distinct transcriptional programme related to endomembrane organization and cellular homeostasis rather than canonical SHH signalling. These findings suggest that PSEN1 may mark a developmentally distinct tumour state and generate new hypotheses regarding subtype-specific developmental programmes in MB.
2026-09-02 | The tumor microenvironment of medulloblastoma: from emerging biological insights to novel therapeutic targeting.
Medulloblastoma is the most common pediatric malignancy of the brain and spine and a major cause of childhood cancer-related morbidity and mortality. Novel therapeutic approaches are urgently needed. The malignant behavior of this disease is influenced both by cell intrinsic factors and by the complex interactions of the tumor cells with its tumor microenvironment. Recent scientific and technological advancements allow increased ability to interrogate the microenvironment in terms of composition and cellular and signaling crosstalk, which together are critical for the regulation of tumor survival, disease proliferation, metastasis, and response to treatment. We summarize the current understanding of the medulloblastoma tumor microenvironment and explore its influence on disease pathogenesis, as well as identify emerging opportunities to leverage the microenvironment as a novel therapeutic target.
2026-06-29 | Medulloblastoma immune microenvironment resembles early brain development and reveals novel basophil- B cell- associated signatures.
Medulloblastoma (MB) is the most common malignant pediatric brain tumor; yet, the mechanisms underlying immune evasion remain poorly understood. Since the developing brain's immune environment naturally promotes tissue tolerance and remodeling, we hypothesized that MB may exploit developmental immune programs to escape surveillance. Here, we aimed to characterize the immune microenvironment of MB compared to healthy brain tissue across different developmental stages. We analyzed RNA-sequencing data from 124 MB tumors and 47 control brain samples spanning postconception weeks (PCWs) 8-37 through adulthood. Using xCell and DeconRNAseq, we quantified enrichment scores for 34 immune cell types and compared their profiles. MB tumors exhibited a distinct immune profile most similar to PCW controls among all age groups tested (P < .001). Key findings included significantly elevated basophils, neutrophils, immature dendritic cells, memory B cells, Th2 cells, and NKT cells in MB samples. Conversely, macrophages (M1 and M2 subtypes), matured dendritic cells, regulatory T cells, and most B cell populations showed reduced enrichment. This pattern suggests a Treg-independent immunosuppressive mechanism. Notably, basophil enrichment in MB was comparable to PCW samples but significantly higher than older controls, potentially explaining the concurrent elevation of memory B cells. MB displays an immune microenvironment resembling early developmental stages, characterized by elevated basophils and memory B cells alongside reduced conventional immune surveillance mechanisms. These findings suggest that MB may co-opt developmental immune tolerance programs and highlight basophil - B cell interactions as potential therapeutic targets. The developmental similarity provides new insights into MB pathogenesis and immune evasion strategies.
small molecules
2026-09-30 | Roles of cuproptosis in central nervous system tumors: from molecular mechanisms to therapeutic prospects.
Cuproptosis is a form of programmed cell death reported in 2022, characterized by copper ions directly binding to mitochondrial lipoylated proteins, inducing aberrant protein aggregation and destabilizing iron-sulfur cluster proteins, ultimately leading to cell death. Distinct from apoptosis, ferroptosis, and other known death modalities, cuproptosis does not rely on classical caspase pathways but exerts its cytotoxic effects by interfering with mitochondrial metabolism. Copper, an essential trace element for humans, maintains its homeostasis through precise regulation by transporters such as CTR1 (copper transporter 1), ATP7A (ATPase copper transporting alpha), and ATP7B (ATPase copper transporting beta). Dysregulated copper metabolism is closely associated with tumor initiation and progression. The central nervous system, being one of the organs with the highest copper content, exhibits heightened sensitivity to copper homeostasis imbalance. During metabolic reprogramming, central nervous system tumors such as glioma and medulloblastoma display enhanced copper dependency, rendering them potential targets for cuproptosis-inducing agents. However, tumor cells can develop resistance to cuproptosis through multiple mechanisms, including upregulation of ATP7A/ATP7B to promote copper efflux, downregulation of FDX1 (ferredoxin 1) and DLAT (dihydrolipoamide S-acetyltransferase) to reduce molecular sensitivity, activation of antioxidant systems such as glutathione, and metabolic switching toward glycolysis. Although several reviews have summarized cuproptosis mechanisms, a comprehensive synthesis focusing specifically on central nervous system tumors remains lacking. This review aimed to systematically examine the molecular basis of copper metabolism and cuproptosis, research progress in various central nervous system tumors, resistance mechanisms and counterstrategies, and cuproptosis-targeted therapeutic approaches. By bridging mechanistic insights with translational challenges unique to neuro-oncology, this review aimed to provide a theoretical foundation for the clinical application of cuproptosis-based therapies and to guide future research directions. Current evidence demonstrates that copper ionophores such as elesclomol and disulfiram, copper-based nanomaterials, and combination strategies with immunotherapy or radiotherapy exhibit promising antitumor efficacy in central nervous system tumor models. Meanwhile, challenges including blood-brain barrier delivery efficiency, normal neuron protection, and elucidation of resistance mechanisms remain major hurdles for clinical translation. The findings of this review could provide a theoretical foundation for the translational application of cuproptosis in neuro-oncology and guide future research directions.
2026-09-26 | The Emerging Role of Ferroptosis in Pediatric Cancer Biology and Therapy.
Ferroptosis is a regulated form of cell death caused by iron-dependent membrane lipid peroxidation. Iron metabolism, membrane lipid composition, cellular metabolic pathways, and antioxidant defense systems regulate ferroptosis. Recently, ferroptosis has attracted interest as a target in cancer therapy, in particular cancer cells have developed several biological adaptative mechanisms to evade ferroptosis, thus enhancing tumor progression, metastatic dissemination, stemness, and resistance to conventional therapies. Interestingly, ferroptosis is regulated by the tumor microenvironment, where hypoxia, immune cells, and stromal components can either stimulate or inhibit ferroptotic cell death. It has been demonstrated that targeting ferroptosis, alone or in combination with chemotherapy, radiotherapy and immunotherapy, has anticancer effects in preclinical models and may contribute to avoid treatment resistance. However, the role of ferroptosis in pediatric cancer remains incompletely understood since these kinds of tumors show different developmental, genomic, and metabolic features that may contribute to create different ferroptosis vulnerabilities. Emerging evidence in neuroblastoma, B-cell acute lymphoblastic leukemia, osteosarcoma, and medulloblastoma supports the involvement of ferroptosis-related pathways in tumor biology and treatment response. Preclinical studies also indicate that ferroptosis induction may represent a therapeutic strategy in selected pediatric cancer models, although tumor heterogeneity, drug delivery, and potential toxicity to developing tissues remain important translational challenges. This review summarizes the molecular mechanisms underlining the relationship between ferroptosis and cancer biology, tumor progression, tumor microenvironment, and therapy resistance, with particular interest in its emerging relevance and therapeutic potential in pediatric oncology, while critically considering the current evidence and major challenges for clinical translation.
2026-09-24 | Preclinical evaluation of ixazomib for high-risk pediatric brain tumors.
Many of the highest risk pediatric brain cancers continue to experience poor clinical outcomes despite intensification of current multimodal therapy. Proteasome inhibition has shown preclinical promise across a range of cancer models including diffuse midline glioma (DMG), medulloblastoma, and atypical teratoid / rhabdoid tumors (ATRT), though clinically viable agents have been limited. Recent studies in adults with glioblastoma suggest that ixazomib, a second-generation proteasome inhibitor, might achieve therapeutic concentrations in the CNS, presenting the opportunity that a CNS penetrant proteasome inhibitor might be similarly leveraged for benefit in childhood brain cancers. Ixazomib was tested against cell lines and orthotopic xenograft models of DMG, Myc-amplified medulloblastoma (Myc-MB), and ATRT. RNA sequencing and LC-MS based proteomics were utilized to define functional consequences of ixazomib treatment in these models. Proteasome activity readouts were used to assess ixazomib activity across brain regions and extracranial solid organs. Ixazomib demonstrates consistent cytotoxic effect across high-risk brain tumor models at low nanomolar concentrations. Ixazomib treatment activates proteostatic stress response and apoptosis. Treatment with ixazomib does not demonstrate survival benefit in orthotopic models, however, and pharmacodynamic testing suggests insufficient inhibition of proteasome activity within the CNS compared to extracranial tissues. While many pediatric brain tumor models demonstrate susceptibility to proteasome inhibition, ixazomib may lack sufficient blood-brain barrier penetration to be a translationally viable means of exploiting this vulnerability.
2026-09-16 | Lipidomic analysis of isolated lipid droplets reveals potential metabolic pathway differences between medulloblastoma subgroups.
Medulloblastomas (MBs) are a highly aggressive paediatric brain tumour which is very difficult to treat. Lipid metabolism has emerged as a crucial determinant of tumour progression, metastasis and therapy resistance in MBs. Lipid droplets (LDs) are lipid-rich organelles that store neutral lipids; their biology and function remain poorly characterised within MBs. MB cells from the low-aggressive Sonic hedgehog (SHH) subgroup (DAOY, UW228-2) and the high-aggressive group 3 (G4) and group 4 (G4) subgroups (D458, D283) were treated with 80 μM oleic acid (OA), 50 μM cholesterol (Chol) or a mix to induce LD formation. LDs were isolated, and lipidomic analysis was performed. No lipid species were consistently upregulated across all cell lines under any treatment condition. SHH cell lines exhibited a broad and consistent lipidomic response across all three treatments, resulting in a pronounced triacylglyceride (TAG) and cholesterol ester (CE) storage profile. The more aggressive subgroups exhibited a more selective, OA-driven phenotype, characterised by longer-chain TAG and CE species. Across all cell lines, OA produced the strongest LD expansion and metabolic separation, whereas Chol elicited a more restricted but highly subgroup-specific signature. G3/G4 Chol responses provide evidence for lipid metabolism rewiring, which could be responsible for the more aggressive phenotype. These findings demonstrate that MB subtypes not only exhibit distinct basal lipid signatures but also engage in fundamentally different lipid remodelling in response to FA overload. These distinct lipid-handling signatures display metabolic heterogeneity across MB subgroups and suggest subtype-specific vulnerabilities. Overall, these findings position LD remodelling as a potential metabolic target of MB cells.
2026-09-09 | Suppression of medulloblastoma by TLR9 activation
Medulloblastoma is an embryonal tumor of the cerebellum that primarily affects children. In recent years, progress has been made in understanding the pathological, genetic, and molecular heterogeneity of medulloblastoma; however, as solid tumors grow in an extraordinarily complex microenvironment, further research into risk classification, prognosis, and treatment is needed. Multiple factors related to tumor pathophysiology, including the immune system, influence tumor growth and the response to chemotherapy. Toll-like receptor agonists have been used, alone or in combination with conventional treatments, to increase tumor chemosensitivity and prolong survival in cancer patients. However, these aspects remain unexplored in the context of medulloblastoma. The present study aimed to determine the effects of administering the synthetic TLR7 and TLR9 agonists on the development of SHH medulloblastoma. We administered the synthetic oligonucleotide (ODN1826) or resiquimod (R848) intratumorally into established subcutaneous xenografts in immunodeficient nu/nu mice and examined their effects on tumor volume and the expression of markers associated with proliferation, apoptotic cell death, and vascularization. Our results showed that treatment with ODN1826 resulted in a significant reduction in tumor volume, accompanied by decreased Ki67 and CD31 expression in tumor tissue, whereas cleaved caspase-3 expression showed a slight, non-significant increase. These findings support further investigation of TLR9 activation as a potential therapeutic strategy for medulloblastoma.
cell therapies
2026-09-29 | Next-generation CAR-T therapy for malignant brain tumors: latest updates from the 2026 AACR Annual Meeting.
The 2026 AACR Annual Meeting showcased rapid progress in chimeric antigen receptor (CAR) T-cell therapy for malignant brain tumors. This correspondence synthesizes 12 clinical and translational abstracts addressing early efficacy, resistance mechanisms, target discovery, and next-generation engineering. Phase I studies in glioblastoma demonstrated feasibility, manageable toxicity, cellular persistence, and preliminary radiographic activity, while revealing antigen loss and treatment-associated myeloid suppression. Longitudinal and spatial analyses further identified limited CAR T-cell persistence, anti-CAR immune responses, and remodeling of suppressive tumor niches. Preclinical strategies sought to overcome these barriers through programmable antigen recognition, alternative KIR/DAP12 signaling, stress-granule modulation, inducible metabolic support, membrane-tethered cytokine agonists, resistance to transforming growth factor beta, and dual targeting of tumor cells and immunosuppressive macrophages. Surfaceome profiling and affinity-guided receptor optimization also identified promising targets in glioblastoma and medulloblastoma. Collectively, these findings support mechanism-informed CAR T-cell platforms, while emphasizing that durability, neurotoxicity, trafficking, immunogenicity, and patient selection require validation in larger clinical studies.
2026-08-08 | CAR T-cell therapy in pediatric brain tumors: a narrative review with comparative analysis of clinical trial eligibility criteria.
Pediatric brain tumors are the leading cause of cancer-related mortality in children, and current standard therapies like surgery, radiotherapy, and chemotherapy offer limited survival benefits and significant long-term morbidity. Chimeric antigen receptor (CAR) T-cell therapy is a transformative treatment for hematologic malignancies and is now being explored for pediatric brain tumors. This review summarizes the latest advances, preclinical and clinical findings, challenges of CAR T-cell therapy, and future directions in pediatric neuro-oncology. 18 studies that met the eligibility criteria were selected, consisting of preclinical models, early-phase clinical trials, and translational studies. A registry search of central nervous system (CNS) tumor trials from Clinicaltrials.gov, ISRCTN, and ANZCTR identified 12 active or completed interventional trials of CAR T-cell therapy in patients with CNS tumors, their eligibility criteria and parameters were compared. Preclinical studies consistently demonstrate that CAR T-cells targeting antigens such as B7-H3, GD2, HER2, IL13Rα2, and EphA2 can induce robust and specific tumor regression in models of medulloblastoma, diffuse intrinsic pontine glioma (DIPG), ependymoma, and high-grade gliomas. On the other hand, B7-H3 is a pan-pediatric target due to its high expression in multiple CNS tumors, including medulloblastoma, ependymoma, and glioma, whereas GD2 is highly relevant for H3K27M-mutant diffuse midline gliomas. Early-phase clinical trials confirm that CAR T-cells can traffic to CNS tumors, infiltrate tumor tissue, and mediate tumor regression. The ICV B7-H3 phase 1 trial in DIPG achieved noteworthy results, with a median survival of 19.8 months across 21 patients and 3 patients surviving more than 40 months. GD2-CAR T-cell therapy in H3K27 M-mutant gliomas showed partial clinical responses, with neurotoxicity and encephalopathy observed, whereas the HER2-targeted locoregional therapy showed no dose-limiting toxicities. Future interventions such as multi-antigen targeting, combinatorial CAR designs, and enhanced cytokine signaling are being developed to improve efficacy and safety. A comparison of 12 registered pediatric CAR T-cell trials showed heterogeneity in eligibility criteria, including age ranges, performance status thresholds, H3K27M mutation requirements, and geographic concentration bias. CAR T-cell therapy holds significant promise for improving outcomes in pediatric brain tumors, but its clinical translation is challenged by tumor heterogeneity, antigen escape, neurotoxicity, and the immunosuppressive tumor microenvironment.
2026-08-07 | Locoregional and systemic adoptive cellular therapies for pediatric brain tumors: a systematic review of CAR‑T, TCR‑engineered T cells, and NK cell strategies.
Adoptive cellular therapies may expand treatment options for pediatric brain tumors by focusing activity on tumor antigens and limiting off-tumor effects. We systematically reviewed preclinical and clinical evidence for CAR T cells, TCR-engineered T cells, and NK or γδ T-cell platforms directed against HER2, B7-H3 (CD276), EGFR806-reactive EGFR, GD2, IL13Rα2, and EphA2 or EphA3, with attention to delivery route, safety, persistence, and combination strategies. Following PRISMA, we searched PubMed, Embase, and Scopus from inception through September 17, 2025, restricted to English. The search yielded 324 records; 103 duplicates were removed; 221 titles and abstracts were screened; 180 full texts were reviewed; and 34 studies were extracted by two independent reviewers. We captured design, tumor and molecular features, product engineering, route and schedule, lymphodepletion, toxicities including cytokine release syndrome, immune effector cell associated neurotoxicity, and tumor inflammation associated neurotoxicity, radiographic or clinical response, survival, and correlatives such as persistence or trafficking in blood, cerebrospinal fluid, or tumor tissue, cytokines, and antigen dynamics. In vivo studies showed reproducible antitumor activity for HER2 in medulloblastoma, GD2 in diffuse midline glioma, and multi-antigen constructs incorporating IL13Rα2 and EphA2 in medulloblastoma and ependymoma, with significant survival advantages compared with controls. γδ T cells targeting the EphA axis selectively killed medulloblastoma with neural sparing; GD2 CAR NK-92 inhibited diffuse intrinsic pontine glioma growth. In early clinical programs, route shaped safety and pharmacodynamics. For GD2, low-dose intravenous induction followed by repeated intraventricular dosing produced objective radiographic regressions and manageable tumor inflammation associated neurotoxicity, while dose-limiting cytokine release syndrome was confined to higher intravenous doses. Intraventricular B7-H3 CAR T cells, given without lymphodepletion, enabled multi-cycle dosing with mainly grade 1 to 2 events and cerebrospinal fluid localized persistence. Weekly intracranial EGFR806 CAR T cells were feasible and well tolerated, with stable disease as the best response in a small cohort. Across trials, persistence and immune activation were most evident in cerebrospinal fluid, supporting cerebrospinal fluid centered pharmacodynamic monitoring. Mechanism-based combinations, including IGF-axis inhibition in diffuse midline glioma and epigenetic priming of GD2 with an integrated safety switch in medulloblastoma, enhanced activity. The evidence supports pediatric-centric antigen selection and a CNS-first, locoregional dosing approach to increase on-tumor exposure and reduce systemic toxicity. Priorities include multi-antigen strategies to prevent escape, incorporation of safety switches, earlier deployment when tumor burden is low, and prospective cerebrospinal fluid pharmacodynamics in multisite phase II studies.
2026-07-27 | Intracerebroventricular B7-H3-targeting CAR T cells for non-pontine DMG and recurrent/refractory pediatric CNS tumors: a phase 1 trial.
High-grade central nervous system (CNS) tumors carry a poor prognosis with limited curative options if first-line therapy fails. B7-H3 is expressed in many of these tumors, and chimeric antigen receptor (CAR) T cell therapy is an emerging immunotherapeutic strategy. BrainChild-03 (NCT04185038) is a single-center, dose-escalation phase 1 study of repeated intracerebroventricular (ICV) B7-H3 CAR T cells in children and young adults with recurrent/refractory CNS tumors (Arms A, B) and diffuse intrinsic pontine glioma (DIPG, Arm C). Here, we report results from Arm B, in which patients with refractory/relapsed CNS tumors or pre- or post-progression non-pontine diffuse midline glioma (DMG) received repeated ICV infusions. Primary objectives were feasibility and safety/tolerability; secondary objectives included CAR T cell detection, disease response, and survival. Of 36 enrolled patients (atypical teratoid rhabdoid tumor n = 5, DMG n = 8, embryonal tumor with multilayer rosettes n = 2, ependymoma n = 4, high-grade glioma n = 6, medulloblastoma n = 8, pineoblastoma n = 3), manufacturing was successful for 35 patients, 26 of whom received therapy. Median age was 10 years (range 1-26). Dose escalation from 1 × 107 to 10 × 107 CAR T cells/dose identified this dose as the maximally tolerated dose regimen, with no dose-limiting toxicities observed. Across 181 total doses (median 7/patient), common adverse events included headache (n = 26), fever (n = 15), and nausea (n = 14). Median survival from first infusion was 11.5 months, ranging from 3.2 months (pineoblastoma, HGG) to 21.4 months (ependymoma); two patients achieved a partial response. Repeated ICV B7-H3 CAR T cell dosing is feasible and tolerable across a spectrum of pediatric CNS tumors, supporting continued investigation in future trials.
2026-06-04 | Tumor Microenvironmental Regulation of CAR T-Cell Therapy in High Risk Medulloblastoma.
B7-H3-directed chimeric antigen receptor (CAR) T cell therapy has demonstrated clinical safety and antitumor activity in pediatric brain tumors (pBTs) but lacks durable responses. Although preclinical studies show efficacy, the CAR designs that best support sustained function in immunosuppressive tumor microenvironments (TMEs) remain unclear. Group 3 medulloblastoma (G3MB) is a lethal pBT with poor responsiveness to immunotherapy. Within the TME, myeloid cells dominate the immune landscape and regulate T cell function through innate immune pathways, including the Toll-like receptor 7/8 (TLR7/8) axis. While TLR7/8 agonists activate antitumor myeloid programs, their integration with CAR T-cell therapy has not been explored. Therefore, we hypothesize that CAR architecture and TLR7/8-mediated myeloid activation cooperatively govern CAR T-cell function and subsequent therapeutic outcomes in G3MB. B7-H3 CARs incorporating CD28, 4-1BB, or dual CD28/4-1BB co-stimulation were evaluated in vitro and in orthotopic G3MB models. Resiquimod was formulated in a brain-penetrant poly (2-oxazoline) nanoparticle (ResiPOx) to activate TLR7/8-expressing myeloid cells. T cell and myeloid states were assessed by flow cytometry, bulk, and single-cell RNA sequencing. CAR designs showed similar tumor control in immunodeficient hosts but diverged in immunocompetent models, where dual-costimulatory CAR T-cells demonstrated superior cytotoxicity and persistence. The optimal CAR induced sustained CAR T-cell cycling and TAM reprogramming while downregulating TLR7/8 in dominant myeloid clusters. ResiPOx enhanced CAR T-cell efficacy by activating myeloid cells and reducing suppressive populations. Optimized CAR design combined with TLR7/8-mediated myeloid reprogramming enhances T cell activity, supporting TME-guided immunotherapy for G3MB.
proteins
2026-09-14 | Local delivery of interferon restores antigen presentation and sensitizes medulloblastoma to T cell killing.
Medulloblastomas are considered immunologically cold and refractory to immunotherapy. One factor contributing to their low immunogenicity is impaired antigen presentation, which allows tumor cells to evade cytotoxic T cells. Using a syngeneic mouse model of medulloblastoma, we demonstrate that despite low expression of MHC class I on tumor cells, depletion of CD8+ T cells accelerates tumor growth, whereas adoptive transfer of tumor-reactive CD8+ T cells prolongs survival. These antitumor effects rely on T cell-derived interferon gamma (IFNγ), which induces MHC class I on tumor cells and facilitates tumor cell killing by T cells. Importantly, delivering IFNγ directly into tumors via convection-enhanced delivery enhances CD8+ T cell-mediated killing of tumor cells and significantly prolongs survival in tumor-bearing mice. These studies highlight the importance of T cells in controlling brain tumors and the value of IFNγ as an adjuvant for T cell-based immunotherapy.
2026-07-10 | Ang2 and TAT targeting of leptomeningeal disease by the intravenous and intrathecal routes: a comparative analysis.
Leptomeningeal disease (LD), involving the metastasis of cells to the leptomeningeal membranes in the central nervous system (CNS), can be a deadly complication of several different types of cancer originating in the periphery or CNS, including breast cancer (BC) and pediatric medulloblastoma (MB). Targeted therapy represents a promising new approach to improve overall survival for LD patients. To this date, angiopep-2 (Ang2) and transactivating transcriptional activator (TAT), two well-known peptides for their brain delivery capability, have been reported to transport therapeutic cargos into the CNS for treatment of disease. Current administration strategies, however, still rely on oral delivery or intravenous injection (IV), where the substances need to travel through complex biological barriers to reach the subarachnoid space (SAS), which is the primary location of LD. Our research group has focused on the intrathecal (IT) route of administration as an alternative approach that can potentially enable high exposure of drug to CSF exposed tissues. However, there is a major field gap in understanding how targeting peptides can access (or not access) LD as a function of their route of administration. Therefore, our work was focused on comparing the targeting capability of Ang2 vs TAT by IT vs IV routes of administration. We first generated two xenograft models of LD by directly infusing breast cancer cells (MDA-MB231) or medulloblastoma cells (HDMB03) into the SAS via intracisternal magna injection (ICM) to form BC-LD and MB-LD models, respectively. These tumor models were characterized for overall survival, tumor growth patterns, and presence of hydrocephalus. Second, we further administered fluorescently labeled Ang2 or TAT peptides either IV or ICM into tumor bearing mice. Neuraxial fluorescence images were examined to evaluate the targeting ability of these two peptides based on colocalization between peptide signal and tumor tissues ex vivo . We discovered that the median survival of both models was negatively related to the number of the cells infused. While HDMB03 cells tended to metastasize preferentially to the brain region, MDA-MB231 cells tended to metastasize preferentially to the spinal cord. Both models present hydrocephalus as one of the common clinical symptoms in LD patients. Compared to the healthy control, MB-LD yielded a 7.3-fold increase and BC-LD a 26.5-fold increase in ventricular volume. Furthermore, targeting achieved by TAT was significantly higher than targeting achieved by Ang2 in thoracic spine for the MB-LD model. For BC-LD model, TAT's signal was found significantly higher than Ang2's signal in olfactory bulbs, brain stem, thoracic spine, and lumbar spine regions. While both peptides showed a strong signal at 2 hours post ICM injection, signal was not detectable 24 hours after administration, reflecting washout or degradation. Significantly, these data provide evidence that ICM will be a preferable route of administration over IV for the purpose of maximally targeting LD.
2026-05-13 | Growth Outcomes and Relapse Risk in Pediatric Medulloblastoma Survivors with and Without Growth Hormone Therapy: A 23-Year Single-Center Cohort Study.
Background: Growth hormone deficiency (GHD) is one of the most common endocrine sequelae in survivors of pediatric medulloblastoma, largely resulting from hypothalamic-pituitary irradiation. Concerns regarding the oncologic safety of growth hormone (GH) replacement have historically limited its use. This study aimed to evaluate growth response to GH therapy and its potential association with tumor relapse in medulloblastoma survivors treated between 2000 and 2023. Methods: We conducted a retrospective single-center cohort study including 74 patients diagnosed with medulloblastoma before 18 years of age. GHD was confirmed by stimulation testing according to standard criteria. Auxological, endocrine, and oncologic data were collected longitudinally. Growth outcomes were compared among patients without GHD (n = 38), patients with untreated GHD (n = 13), and patients with GHD receiving GH treatment (n = 23). Relapse rates were assessed following GH initiation and compared with those of untreated patients. Results: GHD was diagnosed in 48.7% of patients. Baseline height SDS did not differ among groups. Patients with untreated GHD experienced a significant decline in height SDS (-1.93 ± 0.78), whereas GH-treated patients showed a significant increase (+0.39 ± 0.06; p < 0.0001). Final height SDS was significantly lower in untreated GHD patients (-2.45 ± 0.36) compared with GH-treated patients (-1.71 ± 0.68) and patients without GHD (-0.68 ± 0.24; p < 0.0001). No evidence of an increased risk of tumor relapse was observed in association with GH therapy during follow-up. Conclusions: GH replacement significantly improves growth outcomes in medulloblastoma survivors with confirmed GHD without apparent increase in relapse risk when initiated after stable remission. The early identification and multidisciplinary management of GHD are essential components of long-term survivorship care.
2026-05-04 | PC3/Tis21/BTG2 and BTG1 genes: regulators of the cell cycle and neurogenesis, as well as tumor suppressors in malignant brain tumors.
PC3/Tis21/BTG2 and BTG1, prototype members of the BTG/Tob family, are antiproliferative transcriptional cofactors discovered 35 years ago as genes induced by nerve growth factor and phorbol 12-myristate 13-acetate or associated with lymphocytic leukemia. They are today known to serve as developmental regulators in several tissues, including neural cells. Biological functions such as cell division, transcriptional control, DNA repair, and mRNA stability, have been linked to their protein products. We will focus in this review on the effects of PC3/Tis21/BTG2 and BTG1 on brain tumorigenesis and neural development, and on cell cycle and apoptosis. In fact, these genes act as tumor suppressors, and their ability to control tumorigenesis in medulloblastoma and glioma is intrinsically linked to their ability to control the differentiation and proliferation of neural stem and progenitor cells during neurogenesis. Chief function of PC3/Tis21/BTG2 during pre/postnatal and adult neurogenesis is its requirement for the differentiation and migration of neural progenitor cells, in adult hippocampus and subventricular zone-which are the main neurogenic niches where adult neurogenesis occurs-as well as in postnatal cerebellum. Moreover, PC3/Tis21/BTG2 inhibits medulloblastoma onset by promoting the migration and differentiation of cerebellar precursor cells outside the external granular layer, i.e., the proliferative epithelium of the cerebellum, thus diminishing their susceptibility to oncogenic transformation under the influence of Sonic Hedgehog. BTG1, by contrast, primarily functions in neurogenesis to inhibit the proliferation of neural stem and progenitor cells, thereby ensuring the preservation of the cell pool and maintaining the quiescence of medulloblastoma cancer stem cells-known for their persistence against treatments and involvement in tumor relapses-thus preventing their entry in cycle. Furthermore, in glioma, PC3/Tis21/BTG2 enhances apoptosis rates while simultaneously decreasing the migration and invasion of cancerous cells, and lowering the levels of cyclin D1. Similarly, BTG1 contributes to the growth arrest of glioma cells through the regulation of cyclin D1 and p21 expression. PC3/Tis21/BTG2 and BTG1 bind and regulate multiple genes, including Id3, cyclin D1, PRMT1 and the chemokine Cxcl3. These interactions underscore the potential of these cofactors in controlling neurogenesis and tumorigenesis through multiple molecular pathways.
2025-06-01 | COG133 peptide-conjugated lipid nanoparticles sensitize medulloblastoma to radiation therapy in mice.
Medulloblastoma (MB) is a malignant brain tumor that often arises in the cerebellum and has a propensity for spreading to the spinal cord or other parts of the central nervous system (CNS). Craniospinal irradiation (CSI) has long been a cornerstone in the treatment of MB, especially for patients with high-risk or metastatic disease. However, CSI often leads to long-term neurocognitive deficits, including learning disabilities, and growth abnormalities, especially in children. In this study, we aimed to decrease the dose of irradiation and the proliferation of MB by using Volasertib (VSB), a Polo-like kinase 1 (PLK1) specific inhibitor. VSB was highly potent in-vitro with an IC50 of 27.43 nM and 13 nM in HDMB03 and DAOY cells, respectively. However, in the orthotopic MB mouse model, VSB as a free drug did not improve overall survival or decrease tumor burden. Hence, we encapsulated VSB in COG133-conjugated lipid nanoparticles (COG133-LNPs) to circumvent the blood-brain barrier (BBB). We observed that COG-133-LNPs loaded with VSB increased the biodistribution of VSB by three folds than the non-targeted LNPs in the brain. Furthermore, COG133-LNPs along with irradiation decreased tumor burden significantly as compared to VSB or radiation alone. To our observation, COG133-LNPs display high potency in killing MB cells and sensitizing them toward radiation therapy.
oligonucleotides
2026-06-03 | Exploration of miR-326 delivery via biocompatible polymeric nanoparticles in medulloblastoma: A preliminary study.
MicroRNAs play a crucial role in tumorigenesis, functioning as oncogenes or tumor-suppressors while orchestrating the differentiation states of cancer cells. In medulloblastoma, the most common malignant pediatric brain tumor, the downregulation of miR-326 is associated with a loss of tumor suppression that leads to uncontrolled proliferation and survival or de-differentiation. In this study, we explore an innovative approach for microRNA delivery using polycaprolactone/chitosan-based nanoparticles. We evaluate the biocompatibility of the nanocarrier in medulloblastoma cell lines and report results on in vivo nanoparticles administration, demonstrating minimal toxicity in the most exposed organs. In vitro findings reveal that nanoparticles-mediated miR-326 delivery significantly reduces stemness markers (Nanog and Sox2) and promotes neuronal differentiation, as evidenced by increased β3-tubulin expression. These results highlight polycaprolactone-based nanoparticles as a promising platform for miR-326 delivery, establishing a foundation for future investigations on therapeutic strategies in medulloblastoma.
2025-11-07 | The MYC-dependent lncRNA MB3 inhibits apoptosis in Group 3 Medulloblastoma by regulating the TGF-β pathway via HMGN5.
Group 3 (G3) is one of the most common and aggressive subtypes of the paediatric cerebellar tumour Medulloblastoma (MB), primarily driven by the MYC oncogene. The challenging targeting of MYC, coupled with gaps in understanding G3 MB molecular bases, has hindered the development of targeted therapies. The unconventional oncogenic roles of long noncoding RNAs (lncRNAs) offer opportunities to address this complexity, to provide insights and to identify novel targets. Using -omics approaches and molecular/cellular assays, we elucidate the mode-of-action of lncMB3, a MYC-dependent, anti-apoptotic lncRNA in G3 MB. LncMB3 regulates the TGF-β pathway, critically altered in G3 medulloblastomagenesis, via direct binding and translational inhibition of the mRNA for the epigenetic factor HMGN5. This regulatory axis affects apoptosis through photoreceptor lineage genes, including the G3 driver OTX2. The synergistic effects between lncMB3 targeting and cisplatin treatment underscore the relevance of this network. Additionally, we propose novel ferritin-based nanocarriers for the efficient delivery of antisense oligonucleotides against lncMB3. LncMB3 crucially links MYC amplification and apoptosis inhibition through a circuit involving RNA-based mechanisms, G3 MB key determinants and underexplored factors. This integrated framework deepens the understanding of G3 MB landscape and supports the potential for translating lncRNA research into future applications.
2025-06-24 | Delivery of LOXL1-AS1-siRNAs using targeting peptide-engineered extracellular vesicles with focused ultrasound to suppress medulloblastoma metastasis.
Metastasis of medulloblastomas (MBs) is difficult to treat and remains the primary cause of death in children with this brain tumor. Current treatment focuses on radiotherapy to limit metastatic recurrence and maintain survival, but this may cause long-term neurocognitive deficits. This challenge emphasizes the need for novel targeted therapies to combat metastatic MB. In this study, we report an RNA therapy model using targeted extracellular vesicles (EVs) to deliver therapeutic small-interfering (si)RNAs to MB. First, MB-targeted EVs (MB-tEVs) were generated via genetic modification of EV-producing cells to express E1-3, an MB-specific peptide. Next, isolated MB-tEVs were loaded with siRNAs that targeted LOXL1-AS1, a pro-metastatic long non-coding RNA in sonic-hedgehog MB (SHH-MB). Expression of the E1-3 peptide increased MB-tEV internalization into MB cells, where the delivered siRNAs effectively silenced LOXL1-AS1 and suppressed LOXL1-AS1-mediated metastatic traits of SHH-MB cells in vitro. Locoregional application of microbubble-enhanced focused ultrasound (FUS) improved the accumulation of systemically injected EVs in the mouse brain. Mice treated with siRNA-loaded MB-tEVs had decreased LOXL1-AS1 expression, reduced metastases, and improved survival in an SHH-MB orthotopic model. Our study provides the first and very promising evidence for the combined use of tumor-targeted EVs and microbubble-enhanced FUS to deliver therapeutic siRNAs to suppress metastatic MB, potentially supporting conventional treatments and improving clinical outcomes of this malignant pediatric tumor.
2025-02-06 | Integrated interactome, proteomic and functional analyses reveal molecular pathways driving L1TD1-induced aggressiveness in CNS embryonal tumor cells.
L1TD1 is a pluripotency factor required for embryonic stem cell self-renewal; its expression has also been detected in solid tumors, including embryonal tumors of the central nervous system (CNS). Previously, we showed that L1TD1 expression correlates with metastasis formation and shorter overall survival of medulloblastoma patients. Here, we used affinity purification coupled to mass spectrometry to map the L1TD1 interactome, and global proteomics to assess proteins differentially regulated by L1TD1 expression in patient-derived embryonal CNS tumor cell lines. We identified novel L1TD1 interactors and differentially expressed proteins related to cell proliferation, death and motility. Finally, we demonstrated that L1TD1-overexpressing tumor cells have distinct cell morphology with enhanced filopodial formation, higher cell motility, greater proliferation capability, and reduced sensitivity to cisplatin treatment.
2025-01-06 | Tumor Suppressor microRNAs as Potential Treatment Therapeutics for Advanced Medulloblastoma
Medulloblastoma (MB) is one of the most prevalent forms of malignant brain cancer observed within pediatric patients and is particularly difficult to diagnose and treat due to the anatomical localization of tumors near the brainstem. Currently, there are four molecular classifications of MBL: WNT, SHH, Group 3, and Group 4 tumor subgroups. Wingless-type (WNT) mutant tumors are the least common, often caused by mutations in the CTNNB1 gene that plays a crucial role in the wingless cell signaling pathway, yet associates with the best prognosis as compared to all other MBL subtypes. Sonic hedgehog (SHH) mutant tumors arise due to continued release of Shh from purkinje cells, and an uninhibited proliferation response by granular neuronal precursors (GNPs). Group 3 and 4 MBL subgroups are still a molecularly heterogeneous class of tumors, with Group 3 MBL being highly associated with metastasis upon diagnosis, and more prevalently characterized by MYC amplification and activation. Group 4 MBL tumors comprise approximately 40% of all MBL, and remain remarkably heterogeneous with respect to somatic mutations of genes such as KDM6A, OTX2, ZMYM3, with an approximate 80% of tumors harboring chromosome 17 copy number alterations. While a majority of MBL cases cannot be linked to a single protein coding gene alteration, the role of non-coding RNAs, such as miRNAs, seems quite promising as a genetic marker to further sub-categorize MBL at the molecular level. Furthermore, miRNA-based therapy is proving to be a promising treatment to curb the growth of a number of cancer types within the clinic, with particular miRNAs under investigation including miR-34a, miR-211, and miR-584-5p. These miRNAs are known to induce cell cycle arrest in mouse models and demonstrate anti-tumorigenic properties in vitro, meriting further investigation of miRNA-based clinical trials for pediatric MBL patients.
other
2026-09-25 | Divergent medulloblastoma chromatin states disclose KDM2B as a selective dependency.
Medulloblastoma is a biologically heterogeneous childhood cerebellar tumor harboring frequent chromatin-modifying gene alterations. How these alterations promote transcriptional programs governing malignancy remains poorly defined. To address this knowledge gap, we evaluated chromatin states across medulloblastoma subgroups by multi-modal integration of histone modifications with mutational, DNA methylation and transcriptomic profiles. A bivalent/poised enhancer (EnhBiv) state was specifically enriched at the promoters of neurodevelopmental genes in Group 3/4 medulloblastoma. Integrative bioinformatics coupled with chromatin occupancy studies identified aberrant KDM2B binding at EnhBiv-enriched promoters. CRISPR-mediated knockout or acute protein degradation of KDM2B selectively suppressed the growth of medulloblastoma models in vitro and in vivo. Mechanistically, KDM2B promotes sequential recruitment of Polycomb repressive complexes (PRC1/PRC2) and EnhBiv chromatin, thereby repressing neuronal differentiation programs. Collectively, we provide foundational insights into an epigenetic basis of medulloblastoma, nominating KDM2B as a selective dependency in high-risk subgroups that warrants consideration as a candidate therapeutic target.
2026-09-23 | Spatial and single-cell dissection of medulloblastoma identifies developmental hierarchies and a prognostic PPIA-BSG tumor-immune axis.
Medulloblastoma (MB) in children is highly heterogeneous, leading to its classification into molecular subgroups and resulting in significant differences in clinical outcomes even within the same risk group. This heterogeneity severely hampers the clinical management of MB. Therefore, it is essential to characterize MB heterogeneity within its tumor microenvironment. Deep single-cell RNA sequencing (scRNA-seq) was performed on tumor tissues and matched adjacent normal tissues from two WNT, three Group 4 (G4), and one Sonic Hedgehog (SHH) MB patients. In addition, tumor tissue and adjacent cerebellar tissue from one patient in each subgroup were subjected to matched spatial transcriptomic sequencing. A total of 316,446 single cells from MB and adjacent tissues were profiled by scRNA-seq. The cellular characteristics and developmental trajectories of granule cell precursors, unipolar brush cells, neural stem cells, microglia, and immune populations were defined, along with transcriptomic features associated with candidate cells of origin in MB. Infiltrating immune cells were present within tumors and exhibited an activated regulatory T-cell phenotype. Cell-cell communication analysis identified the PPIA-BSG co-receptor as a critical signaling axis in MB. Multiplex immunofluorescence and external bulk transcriptomic validation identified PPIA-BSG co-receptor as an independent prognostic factor. Single-cell transcriptomic analysis delineates the cellular ecosystem of tumor and adjacent tissue-derived populations in MB, with particular emphasis on candidate cells of origin across molecular subgroups. These findings suggest that infiltrating immune cells may provide a foundation for immunotherapeutic strategies in MB and identify PPIA-BSG co-receptor as a potential therapeutic target.
2026-09-15 | PSEN1 Expression Identifies a Developmentally Distinct Favourable-Prognosis State in SHH α Medulloblastoma.
Although PSEN1 is best known for its role in Alzheimer's disease, it also regulates neural development and cerebellar morphogenesis. Medulloblastoma (MB) is the most common malignant paediatric brain tumour and arises from disrupted cerebellar developmental programmes. The clinical significance of PSEN1 in MB remains unknown. We investigated the prognostic value and transcriptional correlates of PSEN1 expression across molecular subgroups and subtypes of MB. Public bulk and single-cell transcriptomic datasets were used to examine PSEN1 expression, associations with overall survival (OS) and transcriptional correlates in MB. The SHH α-associated transcriptional pattern was evaluated in an independent cohort, and PSEN1 expression was further examined in the developing human cerebellum and across paediatric brain tumour types. Genes strongly correlated with PSEN1 in SHH α MB were subjected to gene ontology (GO) enrichment analysis. High PSEN1 expression was consistently associated with significantly longer OS exclusively in SHH α MB. The PSEN1-associated transcriptional pattern was reproduced in an independent SHH α cohort. PSEN1 was expressed across developing cerebellar cell populations and paediatric brain tumour types, with MB showing intermediate expression among the tumour entities examined. In SHH α MB, PSEN1 was associated with a coordinated transcriptional programme enriched for RNA homeostasis, intracellular membrane trafficking, protein quality control, lipid and calcium signalling and developmental pathways. High PSEN1 expression identifies a favourable-prognosis subset of SHH α MB and is associated with a distinct transcriptional programme related to endomembrane organization and cellular homeostasis rather than canonical SHH signalling. These findings suggest that PSEN1 may mark a developmentally distinct tumour state and generate new hypotheses regarding subtype-specific developmental programmes in MB.
2026-09-02 | The tumor microenvironment of medulloblastoma: from emerging biological insights to novel therapeutic targeting.
Medulloblastoma is the most common pediatric malignancy of the brain and spine and a major cause of childhood cancer-related morbidity and mortality. Novel therapeutic approaches are urgently needed. The malignant behavior of this disease is influenced both by cell intrinsic factors and by the complex interactions of the tumor cells with its tumor microenvironment. Recent scientific and technological advancements allow increased ability to interrogate the microenvironment in terms of composition and cellular and signaling crosstalk, which together are critical for the regulation of tumor survival, disease proliferation, metastasis, and response to treatment. We summarize the current understanding of the medulloblastoma tumor microenvironment and explore its influence on disease pathogenesis, as well as identify emerging opportunities to leverage the microenvironment as a novel therapeutic target.
2026-06-29 | Medulloblastoma immune microenvironment resembles early brain development and reveals novel basophil- B cell- associated signatures.
Medulloblastoma (MB) is the most common malignant pediatric brain tumor; yet, the mechanisms underlying immune evasion remain poorly understood. Since the developing brain's immune environment naturally promotes tissue tolerance and remodeling, we hypothesized that MB may exploit developmental immune programs to escape surveillance. Here, we aimed to characterize the immune microenvironment of MB compared to healthy brain tissue across different developmental stages. We analyzed RNA-sequencing data from 124 MB tumors and 47 control brain samples spanning postconception weeks (PCWs) 8-37 through adulthood. Using xCell and DeconRNAseq, we quantified enrichment scores for 34 immune cell types and compared their profiles. MB tumors exhibited a distinct immune profile most similar to PCW controls among all age groups tested (P < .001). Key findings included significantly elevated basophils, neutrophils, immature dendritic cells, memory B cells, Th2 cells, and NKT cells in MB samples. Conversely, macrophages (M1 and M2 subtypes), matured dendritic cells, regulatory T cells, and most B cell populations showed reduced enrichment. This pattern suggests a Treg-independent immunosuppressive mechanism. Notably, basophil enrichment in MB was comparable to PCW samples but significantly higher than older controls, potentially explaining the concurrent elevation of memory B cells. MB displays an immune microenvironment resembling early developmental stages, characterized by elevated basophils and memory B cells alongside reduced conventional immune surveillance mechanisms. These findings suggest that MB may co-opt developmental immune tolerance programs and highlight basophil - B cell interactions as potential therapeutic targets. The developmental similarity provides new insights into MB pathogenesis and immune evasion strategies.
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Drug Discovery Landscape
9 orphan drug designations for Medulloblastoma.
9 orphan drug designations for Medulloblastoma.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
silmitasertib | small molecules | FDA | Senhwa Biosciences, Inc. | |
Lutetium (177Lu) omburtamab barzuxetan | antibodies | EMA | Y-Mabs Therapeutics A/S | |
genetically engineered herpes simplex virus | gene therapies | FDA | — | Aettis, Inc. |
2-Amino-4-[11C]methylsulfanyl-butanoic acid, l-[S methyl[11C]methionine | small molecules | FDA | — | Advanced Imaging Projects, LLC |
Humanised IgG1 monoclonal antibody against the receptor-binding site of human placental growth factor | antibodies | EMA | Oncurious NV | |
1,2:5,6-dianhydrogalactitol | small molecules | FDA | — | DelMar Pharmaceuticals, Inc. |
N-acetylcysteine and sodium thiosulfate | — | FDA | — | Edward A. Neuwelt, MD |
sonidegib | small molecules | FDA | Novartis Pharmaceuticals Corp. | |
16-base single-stranded peptide nucleic acid oligonucleotide linked to 7-amino acid peptide | oligonucleotides | EMA | — | Biogenera SpA |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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