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
4,066 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:
4,066 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:
2026-08-14 | EZH2 Inhibition and Myeloid Risk: A Feature of On-Target Biology.
In March 2026, Ipsen voluntarily withdrew the EZH2 inhibitor tazemetostat (Tazverik) from all markets and indications following results from the confirmatory Phase Ib/III SYMPHONY-1 trial demonstrating hematologic second primary malignancies (SPMs) in 5.7% of treated patients, compared with none in the control arm. The most frequently reported SPMs were myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Although this finding may be interpreted as an idiosyncratic liability of a single agent, the biology of EZH2 suggests a broader, target-driven risk. EZH2 functions in a context-dependent manner as both an oncogene and a tumor suppressor. Gain-of-function mutations drive transformation in germinal center B-cell lymphomas, whereas loss-of-function alterations impair hematopoietic stem cell differentiation and are recurrent in myeloid malignancies, including MDS and AML. In selected solid tumor contexts, such as specific subtypes of medulloblastoma, EZH2 loss can likewise promote tumorigenesis. These observations raise concern that chronic pharmacologic inhibition of EZH2 may phenocopy loss-of-function states that initiate myeloid neoplasia. We argue that the withdrawal of tazemetostat exposes a fundamental vulnerability in the development of epigenetic therapies: target validation has focused on tumor-intrinsic effects while underweighting consequences in normal stem cell compartments. This issue is particularly relevant for ongoing Phase III programs in prostate cancer, where prolonged exposure may amplify latency-dependent risks. We propose changes to preclinical safety assessment, trial design, and pharmacovigilance to mitigate predictable, target-mediated toxicities.
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.
2026-07-29 | Precision medicine directed therapy enabling long-term survival in medulloblastoma: a case report.
Subgroup-SHH of medulloblastoma (MB) is primarily found in children, with an increased propensity for metastatic presentation that contributes to its poor prognosis. Current therapy approaches may include surgery, radiation, systematic chemotherapy, and autologous stem cell transplant (ASCT). At relapse, patients may receive additional chemotherapy and radiation if possible. The outcome for relapsed patients is 10-30% long term survival. Herein we present a case of a 6-year-old male with a pathologically confirmed diagnosis of subgroup-SHH MB, who was treated with upfront surgical resections, high-dose chemotherapy, and ASCT. Nine months after completion of upfront therapy, the subject relapsed. Subsequently, he was enrolled onto NMTRC009 (NCT02162732) and underwent biopsy with genomic sequencing (DNA whole exome and RNA transcriptome). A molecular tumor board, using precision medicine analysis, recommended vorinostat, vismodegib, curcumin, and palbociclib as targeted therapy. This therapy resulted in a complete tumor response and long-term survival. A cell line was derived from the subject's tumor and used for in vitro testing. Combined molecular therapies demonstrated synergistic efficacy compared with single-agent treatment.
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.
2026-08-14 | EZH2 Inhibition and Myeloid Risk: A Feature of On-Target Biology.
In March 2026, Ipsen voluntarily withdrew the EZH2 inhibitor tazemetostat (Tazverik) from all markets and indications following results from the confirmatory Phase Ib/III SYMPHONY-1 trial demonstrating hematologic second primary malignancies (SPMs) in 5.7% of treated patients, compared with none in the control arm. The most frequently reported SPMs were myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Although this finding may be interpreted as an idiosyncratic liability of a single agent, the biology of EZH2 suggests a broader, target-driven risk. EZH2 functions in a context-dependent manner as both an oncogene and a tumor suppressor. Gain-of-function mutations drive transformation in germinal center B-cell lymphomas, whereas loss-of-function alterations impair hematopoietic stem cell differentiation and are recurrent in myeloid malignancies, including MDS and AML. In selected solid tumor contexts, such as specific subtypes of medulloblastoma, EZH2 loss can likewise promote tumorigenesis. These observations raise concern that chronic pharmacologic inhibition of EZH2 may phenocopy loss-of-function states that initiate myeloid neoplasia. We argue that the withdrawal of tazemetostat exposes a fundamental vulnerability in the development of epigenetic therapies: target validation has focused on tumor-intrinsic effects while underweighting consequences in normal stem cell compartments. This issue is particularly relevant for ongoing Phase III programs in prostate cancer, where prolonged exposure may amplify latency-dependent risks. We propose changes to preclinical safety assessment, trial design, and pharmacovigilance to mitigate predictable, target-mediated toxicities.
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.
2026-07-29 | Precision medicine directed therapy enabling long-term survival in medulloblastoma: a case report.
Subgroup-SHH of medulloblastoma (MB) is primarily found in children, with an increased propensity for metastatic presentation that contributes to its poor prognosis. Current therapy approaches may include surgery, radiation, systematic chemotherapy, and autologous stem cell transplant (ASCT). At relapse, patients may receive additional chemotherapy and radiation if possible. The outcome for relapsed patients is 10-30% long term survival. Herein we present a case of a 6-year-old male with a pathologically confirmed diagnosis of subgroup-SHH MB, who was treated with upfront surgical resections, high-dose chemotherapy, and ASCT. Nine months after completion of upfront therapy, the subject relapsed. Subsequently, he was enrolled onto NMTRC009 (NCT02162732) and underwent biopsy with genomic sequencing (DNA whole exome and RNA transcriptome). A molecular tumor board, using precision medicine analysis, recommended vorinostat, vismodegib, curcumin, and palbociclib as targeted therapy. This therapy resulted in a complete tumor response and long-term survival. A cell line was derived from the subject's tumor and used for in vitro testing. Combined molecular therapies demonstrated synergistic efficacy compared with single-agent treatment.
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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
9 orphan drug designations for Medulloblastoma.
9 orphan drug designations for Medulloblastoma.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
silmitasertib | small molecules | FDA | 2021-12-15 | — | Senhwa Biosciences, Inc. |
Lutetium (177Lu) omburtamab barzuxetan | antibodies | EMA | 2021-07-19 | — | Y-Mabs Therapeutics A/S |
genetically engineered herpes simplex virus | gene therapies | FDA | 2019-05-09 | — | Aettis, Inc. |
2-Amino-4-[11C]methylsulfanyl-butanoic acid, l-[S methyl[11C]methionine | small molecules | FDA | 2017-01-17 | — | Advanced Imaging Projects, LLC |
Humanised IgG1 monoclonal antibody against the receptor-binding site of human placental growth factor | antibodies | EMA | 2017-01-12 | — | Oncurious NV |
1,2:5,6-dianhydrogalactitol | small molecules | FDA | 2016-03-10 | — | DelMar Pharmaceuticals, Inc. |
N-acetylcysteine and sodium thiosulfate | — | FDA | 2015-08-31 | — | Edward A. Neuwelt, MD |
sonidegib | small molecules | FDA | 2015-03-23 | — | Novartis Pharmaceuticals Corp. |
16-base single-stranded peptide nucleic acid oligonucleotide linked to 7-amino acid peptide | oligonucleotides | EMA | 2010-10-01 | — | Biogenera SpA |
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