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Principal Investigator: NAGI G AYAD
Organization: GEORGETOWN UNIVERSITY
Fiscal Year: 2024
Award: $234,000
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Despite considerable advances in identifying genetic and epigenetic abnormalities in medulloblastoma, many
patients succumb to the disease. In addition, patients who respond to traditional therapy suffer from cognitive
and intellectual deficits. Therefore, there is a dire need to identify novel therapies for treating medulloblastoma.
Rho family GTPases are targets in multiple cancers including medulloblastoma. Rho, Rac1 and Cdc42 are
essential mediators of cell-cell adhesion and cellular motility signaling, which are dysregulated in
medulloblastoma. These GTPases are involved in the regulation of the cytoskeleton, cell migration, cellular
proliferation, and developmental signaling. The small GTPase Rac1 has recently been reported as a possible
therapeutic target in medulloblastoma due to its regulation of Hedgehog signaling via the GLI1 and GLI2
transcription factors. We have recently reported that GLI1/GLI2 are in a novel complex that contains the
epigenetic regulators UHRF1 and DNMT1. Therefore, Rac1 may play a previously unappreciated role in
epigenetic regulation of medulloblastoma by controlling the GLI1/GLI2/UHRF1/DNMT1 complex. To test this, we
will utilize a novel brain penetrant Rac1 inhibitor we developed termed GYS32661. We will test the hypothesis
that GYS32661 will reduce GLI1/GLI2 nuclear localization, attenuate Shh signaling in medulloblastoma in vitro
(Aim 1) and reduce medulloblastoma growth in vivo (Aim 2). Collectively, our studies will test whether Rac1
inhibition is a novel therapeutic strategy for treating medulloblastoma.
Terms: <0-11 years old><Adolescent><Adolescent Youth><Affect><After Care><After-Treatment><Aftercare><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Apopain><Apoptosis><Apoptosis Pathway><Apoptosis-Related Cysteine Protease Caspase 3><Assay><Ataxia><Ataxy><Attenuated><Basal Transcription Factor><Basal transcription factor genes><Binding><Bioassay><Biological Assay><Brain><Brain Cancer><Brain Nervous System><Breast Cancer Cell><CASP-3><CASP3><CASP3 gene><CPP-32><CPP32><CPP32 protein><CPP32B><CPP32beta><Cancers><Cell Body><Cell Communication and Signaling><Cell Cycle><Cell Cycle Progression><Cell Division Cycle><Cell Growth in Number><Cell Locomotion><Cell Migration><Cell Movement><Cell Multiplication><Cell Nucleus><Cell Proliferation><Cell Signaling><Cell-Cell Adhesion><Cells><Cellular Matrix><Cellular Migration><Cellular Motility><Cellular Proliferation><Cerebellum><Child><Child Youth><Children (0-21)><Clinical Trials><Closure by Ligation><Cognitive><Colorectal Cancer><Complex><Coordination Impairment><Cysteine Protease CPP32><Cysteine Protease CPP32 Gene><Cytoskeletal System><Cytoskeleton><Data><Development><Disease><Disorder><Dissociation><Dose><Drugs><Dyssynergia><Encephalon><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Expression Signature><Family><Foundations><GLI Family Gene><GLI Family Protein><GLI Protein><GLI gene><GLI-Kruppel Family Member 2><GLI1><GLI1 Gene><GLI1 Protein><GLI2><GLI2 gene><GTP Phosphohydrolases><GTPases><Gene Expression Profile><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genetic><Gli2 protein><Glioma Associated Oncogene Homolog 1 Protein><Glioma Associated Oncogene Homolog Protein><Glioma-Associated Oncogene Homolog><Growth><Guanosine Triphosphate Phosphohydrolases><Guanosinetriphosphatases><H and E><Hedgehog (Hh) signal transduction pathway><Hematoxylin and Eosin><Hematoxylin and Eosin Staining Method><Immune Precipitation><Immunofluorescence><Immunofluorescence Immunologic><Immunoprecipitation><In Situ Nick-End Labeling><In Vitro><Incidence><Intracellular Communication and Signaling><Laboratories><Ligation><Luciferase Immunologic><Luciferases><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Measures><Mediator><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Medicine><Medulloblastoma><Mice><Mice Mammals><Modeling><Molecular Interaction><Monitor><Monomeric G-Proteins><Monomeric GTP-Binding Proteins><Murine><Mus><NMR Imaging><NMR Tomography><Neurologic Deficit><Neurosphere><Nuclear><Nuclear Magnetic Resonance Imaging><Nucleus><PARP Cleavage Protease><PARP Cleavage Protease Gene><Pathway interactions><Patients><Perfusion><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase><Play><Programmed Cell Death><Proliferating><RNA Seq><RNA sequencing><RNAseq><Recurrence><Recurrent><Regulation><Reporter><Reporting><Role><SCA-1><SCA-1 Gene><SHH><SHH gene><SREBP Cleavage Activity 1><SREBP Cleavage Activity 1 Gene><Safety><Signal Transduction><Signal Transduction Systems><Signaling><Small G-Proteins><Small GTPases><Sonic Hedgehog><Staining method><Stains><System><TUNEL><Testing><Tissue Growth><Toxic effect><Toxicities><Transcription Factor Proto-Oncogene><Transcription factor genes><Visualization><Yama><Yama protein><Zeugmatography><attenuate><attenuates><biological signal transduction><breast tumor cell><caspase-3><cell motility><cysteine protease P32><developmental><drug/agent><efficacy testing><epigenetic regulation><epigenetically><gene expression pattern><gene expression signature><gli2 gene product><glioma associated oncogene 1><glioma associated oncogene family zinc finger 1><glioma associated protein 2><guanosinetriphosphatase><hedgehog signaling><hedgehog signaling pathway><hh signaling pathway><in vivo><inhibitor><intracellular skeleton><juvenile><juvenile human><kids><malignancy><migration><model of animal><mouse model><murine model><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><ontogeny><pathway><pharmaceutical><pharmacologic><post treatment><resistance mechanism><resistant mechanism><rho><small molecular inhibitor><small molecule inhibitor><smoothened signaling pathway><social role><standard of care><terminal nick end labeling><therapeutic target><traditional therapy><transcription factor><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><treatment group><tumor><tumor growth><youngster>