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Principal Investigator: Yanxin Pei
Organization: CHILDREN'S RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $507,610
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary
Medulloblastoma (MB) is the most common malignant brain tumor in children. There are several subtypes of MB,
and among them, the GLI2-amplified SHH-MB subtype has the worst prognosis and a poor survival rate; the 5-
year survival rate is <30%. Moreover, the GLI2-amplified MBs are non-responsive to the only targeted treatment
option available for SHH-MB, the SMO inhibitors. This leaves an unmet critical treatment gap, and there is an
urgent need to identify novel targets to develop effective therapeutics. However, a deeper understanding of the
cellular and molecular mechanisms driving GLI2-amplified MB tumorigenesis is currently lacking. With a focused
goal to resolve this particular type of MB tumorigenesis, we recently generated an engineered mouse model of
GLI2-driven MB. Using this model, we demonstrated that GLI2 is the critical driver of tumorigenesis and identified
granule cell progenitors (GCPs) as the cells of origin. Interestingly, we have also found that GLI2 drives only
Math1+ embryonic GCPs but not neonatal GCPs to form SHH-MB. Correspondingly, our scRNA-seq analysis
revealed that the MAPK pathway is specifically enriched in embryonic but not neonatal Math1+ GCPs. Moreover,
the MAPK pathway is activated in mouse and human GLI2-driven MB tumors, and a MEK/ERK inhibitor
significantly delayed the growth of GLI2-driven MB in vivo. Based on these exciting preliminary data, we put
forward a novel hypothesis that GLI2-driven MB originates from a specific cell population of Math1+
GCPs and in a particular spatiotemporal window during cerebellar development. Therefore, targeting
MAPK/MEK/ERK pathway in the embryonic GCPs in a specific timeframe can effectively prevent GLI2-
driven MB initiation and progression. In this proposal, we plan to use our new GLI2-driven MB transgenic
mouse model to define the spatiotemporal window of tumorigenesis of GLI2-driven MB more precisely and
establish whether MAPK/MEK/ERK signaling is required for GLI2-driven MB initiation and development.
Furthermore, we will use GLI2-amplified MB patient-derived xenograft (PDX) models to evaluate the efficacy of
MEK/ERK inhibitors in preventing tumor progression and examine the mechanisms underlying therapeutic
resistance. We will pursue our ultimate goal to design novel therapeutics and achieve better treatment outcomes
by targeting MAPK/MEK/ERK pathway and via identifying additional combinational therapeutic opportunities to
fight against tumor relapse. Since aberrant expression of GLI2 occurs in a number of other tumor types, our
studies will also set a precedent for all GLI2-driven malignancies.
Terms: <0-11 years old><Antioncogene Protein p53><Automobile Driving><Basal Transcription Factor><Basal transcription factor genes><Bone-Derived Transforming Growth Factor><Brain Cancer><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Tumor Antigen P53><Cerebellum><Cessation of life><Child><Child Youth><Childhood Malignant Brain Tumor><Childhood Neoplasm><Childhood Tumor><Children (0-21)><Clinical><Combined Modality Therapy><Cytoplasmic Granules><Data><Death><Development><Disease><Disorder><Doxycycline><ERK 1><ERK1><ERK1 Kinase><Early Diagnosis><Embryo><Embryonic><Engineering><Extracellular Signal-Regulated Kinase 1><Extracellular Signal-Regulated Kinase Gene><GLI-Kruppel Family Member 2><GLI2><GLI2 gene><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Gli2 protein><Goals><Growth><Human><IRES><Internal Ribosome Entry Segment><Internal Ribosome Entry Site><Intracellular Communication and Signaling><MAP Kinase 3><MAP Kinase Gene><MAPK><MAPK3><MAPK3 Mitogen-Activated Protein Kinase><MAPK3 gene><MEKs><MYCN><MYCN gene><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Math><Mathematics><Medulloblastoma><Mice><Mice Mammals><Milk Growth Factor><Mitogen-Activated Protein Kinase 3><Mitogen-Activated Protein Kinase 3 Gene><Mitogen-Activated Protein Kinase Gene><Modeling><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Mouse Strains><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mutation><NMYC><NMYC Gene><Neural Stem Cell><Oncogenesis><Oncogenic><Oncoprotein p53><P44ERK1><P53><PDX model><PSTkinase p44mpk><Pathway interactions><Patient derived xenograft><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pediatric Malignant Brain Tumor><Pediatric Neoplasm><Pediatric Tumor><Phase><Phosphoprotein P53><Phosphoprotein pp53><Phosphorylation><Platelet Transforming Growth Factor><Population><Progenitor Cells><Prognosis><Protein Phosphorylation><Protein TP53><Relapse><Resistance><Resistance development><Resistant development><Ribosome Entry Site><Role><SHH><SHH gene><Signal Transduction><Signal Transduction Systems><Signaling><Sonic Hedgehog><Subgroup><Survival Rate><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><TP53><TP53 gene><TRP53><Testing><Therapeutic><Time><Tissue Growth><Transcription Factor Proto-Oncogene><Transcription factor genes><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Transgenic Mice><Treatment outcome><Tumor Protein p53><Tumor Protein p53 Gene><Tumor-Derived><Vibramycin><Work><aged><alpha-6-Deoxyoxytetracycline><biological signal transduction><cancer progression><childhood brain cancer><combat><combination therapy><combined modality treatment><combined treatment><design><designing><determine efficacy><developing resistance><developmental><driving><early detection><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><fighting><gene signatures><genetic signature><genome mutation><gli2 gene product><glioma associated protein 2><granule><granule cell><improved><in vivo><inhibitor><kids><loss of function mutation><malignancy><molecular profile><molecular signature><mouse model><multi-modal therapy><multi-modal treatment><murine model><neoplasm progression><neoplasm/cancer><neoplastic progression><nerve stem cell><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neuron progenitors><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuroprogenitor><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><p44 MAPK><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathway><patient derived xenograft model><patient oriented outcomes><pediatric brain cancer><pharmacologic><prevent><prevent relapse><preventing><protein p53><relapse prevention><resistance to therapy><resistant><resistant to therapy><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><spatiotemporal><stem cells><survival outcome><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapeutically effective><therapy resistant><transcription factor><treatment resistance><tumor><tumor growth><tumor progression><tumor xenograft><tumorigenesis><tumors in children><youngster>