Identifying innovative synergistic strategies for targeted therapy of MYC-driven medulloblastoma using advanced 3D models and multi-omics analysis

• Applicant: Dr. Nan Qin
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Hematology, Oncology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570897484

Resistance to chemotherapy represents a prevalent cause of treatment failure among cancer patients and constitutes a significant challenge in contemporary cancer research. Both cytotoxic chemotherapeutics and targeted therapies can exhibit similar mechanisms of resistance, including alterations in drug targets, activation of pro-survival pathways, reactivation of signaling cascades, and ineffective induction of apoptosis. Consequently, a systematic characterization of drug resistance through the reactivation or activation of these pathways may facilitate the development of innovative therapeutic strategies. This study will concentrate on MYC-mediated drug resistance, given that the transcription factor MYC is aberrantly activated in numerous cancers, including pediatric malignant brain tumors such as medulloblastoma (MB). The MYC oncogene is the most commonly amplified gene in MB, particularly driving tumorigenesis in Group 3 MB, the most aggressive subtype of this cancer. Therefore, our primary objective is to identify and validate the molecular mechanisms that underpin drug resistance in MYC-driven MB. In our preliminary studies, we identified the HDAC inhibitor Entinostat as a promising therapeutic agent for MYC-driven MB. Utilizing genome-wide dCas9-based transcriptional activation screening, our findings strongly indicate that the activation of the TGFB1/Erk/MKNK1 signaling pathway diminishes the sensitivity of MYC-driven MB cells to Entinostat. Targeting the TGFB1/Erk/MKNK1 signaling pathway in conjunction with MYC may yield a novel therapeutic option for MYC-driven brain cancers. Based on our initial findings, we will validate the role of the TGFB1/Erk/MKNK1 signaling pathway in Entinostat resistance through the use of well-established tumor-initiating cells and more physiologically relevant three-dimensional models. Furthermore, by employing single-cell RNA sequencing and multiplexed spatial proteomics, we will thoroughly characterize the clonal and spatial changes in heterogeneous cell populations. This investigation will enable us to identify regions and subclones where treatment fails to exert its effects, thereby uncovering spatial biomarkers to refine combination therapies. Ultimately, we aim to provide comprehensive preclinical evidence to advance a novel synergistic targeted therapy approach toward clinical application.

• DFG Programme: Research Grants