Targeting MYC in High-Risk Medulloblastoma (MYCMB)

Exploiting High MYC Expression as a Potential Vulnerability for Treatment of High-Risk Medulloblastoma

Medulloblastoma is the most common malignant brain tumor in children. Group 3 medulloblastoma (G3 MB) represents the most aggressive molecular subtype and is associated with poor prognosis, particularly in cases characterized by high expression or amplification of the MYC oncogene. Current treatment strategies are not tailored to this subgroup and are associated with significant long-term toxicities, highlighting the need for more specific therapeutic approaches.

This study aims to characterize biological processes and molecular pathways driven by high MYC expression in high-risk G3 medulloblastoma in order to identify potential therapeutic vulnerabilities. The study will investigate MYC-associated regulation of gene expression and RNA splicing in tumor cells and will define molecular dependencies that may be targeted using candidate or repurposed anticancer agents.

To achieve this, publicly available genomic datasets will be analyzed, findings will be validated in patient tumor specimens, and patient-derived three-dimensional (3D) tumor models will be established from surgical samples. These models will be used for ex vivo assessment of selected therapeutic strategies in a system that preserves key features of the original tumor.

This translational approach integrates computational analyses, molecular validation, and functional testing in patient-derived models to improve understanding of MYC-associated tumor biology in Group 3 medulloblastoma.

Study Overview

• Status: Not yet recruiting
• Conditions: Medulloblastoma
• Intervention / Treatment: Procedure: Tumor tissue collection

Detailed Description

Group 3 medulloblastoma (G3 MB) is the most aggressive molecular subgroup of medulloblastoma and is associated with poor prognosis, particularly in tumors characterized by MYC amplification or high MYC expression. Despite multimodal treatment including surgery, chemotherapy, and craniospinal irradiation, overall survival remains limited and survivors frequently experience significant long-term treatment-related toxicities. Given the largely undruggable nature of MYC, identifying MYC-dependent biological processes that can be therapeutically targeted represents an unmet clinical need.

This study investigates molecular mechanisms underlying MYC-driven tumor aggressiveness and aims to identify actionable vulnerabilities in high-risk G3 medulloblastoma. The project integrates retrospective molecular analyses, prospective collection of tumor specimens, transcriptomic data mining, and functional validation using patient-derived models.

Publicly available RNA sequencing datasets will be analyzed to compare tumors with high versus low MYC expression. Differential gene expression and alternative splicing analyses will be integrated with existing experimental datasets from MYC-depleted medulloblastoma models to identify MYC-regulated pathways and molecular processes.

Candidate genes and molecular signatures identified through bioinformatic analyses will be validated in retrospective tumor specimens using quantitative gene expression assays and evaluation of MYC-associated transcriptional and splicing programs.

In parallel, tumor samples collected from prospectively enrolled patients undergoing standard-of-care surgical resection will be used to establish patient-derived three-dimensional (3D) cultures. These models will be characterized histologically and molecularly to assess concordance with the corresponding primary tumors. Only models that retain key histological and genomic features will be used for downstream functional studies.

Patient-derived 3D cultures will be used as ex vivo platforms to evaluate therapeutic strategies targeting MYC-dependent pathways identified in molecular analyses. Selected compounds will be tested individually or in combination using assays measuring cell viability, proliferation, and survival.

This study does not involve investigational medicinal products or medical devices. All clinical procedures, including surgery and tissue collection, are performed according to standard clinical practice, without additional interventions for research purposes.

This translational project integrates computational analyses, molecular validation, and functional testing in patient-derived models to improve understanding of MYC-driven tumor biology in Group 3 medulloblastoma. The molecular insights generated may also be relevant to other pediatric and adult malignancies characterized by MYC dysregulation.

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Gianpiero Tamburrini; Phone Number: +393349468776; Email: gianpiero.tamburrini@policlinicogemelli.it

Study Locations

• Italy
  • Lazio
    • Rome, Lazio, Italy, 00168
      • Fondazione Policlinico Universitario "A. Gemelli", IRCCS - UOC Neurochirurgia Infantile
      • Contact: GIANPIERO TAMBURRINI, MD; Phone Number: 00393349468776; Email: gianpiero.tamburrini@policlinicogemelli.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with histologically confirmed Group 3 medulloblastoma (G3 MB)
• Age between 0 and 20 years
• Undergoing surgical treatment at the UOC Child Neurosurgery Unit, Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Rome
• Availability of tumor tissue obtained during standard-of-care surgical resection for molecular analyses and/or establishment of patient-derived organoids
• Written informed consent provided by the patient and/or parent/legal guardian (prospective cohort)
• Inclusion of retrospective cases in accordance with applicable Italian privacy regulations (Art. 110-bis)

Exclusion Criteria:

• None

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Medulloblastoma tissue collection and ex vivo translational research; Participants with medulloblastoma undergoing standard-of-care surgical resection will be enrolled after informed consent. Tumor tissue collected during surgery will be used to generate patient-derived organoids (PDOs) for ex vivo translational research. Analyses will include molecular characterization, transcriptomic profiling, and evaluation of tumor cell responses to selected anticancer compounds in preclinical assays. No investigational drugs or medical devices are administered to participants, and no additional clinical procedures beyond routine care are performed.

Procedure: Tumor tissue collection; Tumor tissue will be collected during standard-of-care surgical resection of medulloblastoma. No additional surgical procedures will be performed for research purposes. Collected tissue will be used for molecular analyses and the establishment of patient-derived three-dimensional (3D) cultures for ex vivo translational research, including characterization of MYC-associated molecular pathways and evaluation of tumor cell responses to selected compounds in preclinical assays.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Successful establishment of patient-derived organoids (PDOs) from medulloblastoma surgical specimens	Rate of successful generation of patient-derived organoids (PDOs) from freshly resected high-risk Group 3 medulloblastoma surgical specimens. Success will be defined by the ability of tumor samples to generate stable and expandable three-dimensional (3D) cultures in vitro. Established models will be evaluated for histological and molecular concordance with the corresponding parental tumors using standard pathological and genetic analyses.	Up to 24 months

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Investigators: Principal Investigator: Gianpiero Tamburrini, Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2029

Study Registration Dates

• First Submitted: July 3, 2026
• First Submitted That Met QC Criteria: July 3, 2026
• First Posted (Actual): July 10, 2026

Study Record Updates

• Last Update Posted (Actual): July 10, 2026
• Last Update Submitted That Met QC Criteria: July 3, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Medulloblastoma; Gene Expression; Transcriptomics; MYC; MYC Amplification; Organoids; Group 3 Medulloblastoma; RNA Splicing; Patient-Derived 3D Cultures
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Medulloblastoma
• Other Study ID Numbers: 27529

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No