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Principal Investigator: Viral Oza
Organization: UNIVERSITY OF KENTUCKY
Fiscal Year: 2024
Award: $35,602
Funding agency: National Cancer Institute
PROJECT SUMMARY
Diffuse midline gliomas with H3K27M alteration (DMG-H3K27M) are the leading cause of pediatric
brain tumor-associated deaths. All DMG-H3K27M becomes resistant to radiation, the standard of care, and
most children succumb to their disease within two years of diagnosis. New treatment options are urgently
needed. The applicant's long-term goal is to combine engineering and cancer cell biology to lead a research
group that advances extracellular vesicle (EV)-based drug delivery for central nervous system diseases like
DMG-H3K27M. EVs are potent signaling vehicles in the tumor microenvironment and are understudied in
DMG-H3K27M. The overall objectives are to define how DMG-H3K27M derived EVs contribute to radiation
resistance within a heterogenous tumor and to develop EVs as a delivery vehicle for brain-penetrant
radiosensitizers while equipping the applicant with the skills to become a strong, independent cancer
researcher. Preliminary data show that some subclones within DMG-H3K27M are inherently radiation resistant
and can release EVs readily taken up by radiosensitive cells in a receptor-mediated manner. These EVs
protect the recipient tumor cells from radiation-induced cell death. Therefore, the central hypothesis is that the
cargo of DMG-H3K27M extracellular vesicles, particularly microRNAs, drives radiation resistance within these
tumors and that targeting these factors can sensitize DMG-H3K27M cells to radiotherapy. Additionally, the
selective uptake of EVs by DMG-H3K27M cells suggests that EVs can be exploited as a drug delivery tool. The
rationale is that this research will provide novel insights into mechanisms of radioresistance in DMG-H3K27M
and may result in new approaches to target this cancer. The hypothesis will be tested by pursuing two specific
aims: 1) Determine the mechanism of EV-mediated radioresistance in DMG-H3K27M and 2) Engineer
extracellular vesicles to selectively target brain tumor cells and deliver radiosensitizers. The first aim will be
carried out as part of the dissertation research and will use patient-derived DMG-H3K27M cells, proteomics
approaches, and chemical inhibitors to define the mechanism of EV uptake. miRNA mimics and antagomirs will
also be used to overexpress and silence miRNAs found in EV cargo released from radioresistant cells to
identify miRNAs that confer enhanced radioresistance in DMG-H3K27M. Targets will be validated using
zebrafish xenograft models. The second aim will encompass the post-doctoral research and focus on using
single-cell microfluidic methods to engineer non-tumor extracellular vesicles for specificity towards brain tumor
cells and assessing their capability to cross the blood-brain barrier to deliver radiosensitizers. The research
proposed in this application is significant because it will provide new insights into the role of tumor
heterogeneity in driving therapy resistance. This project will also identify new mechanisms of DMG-H3K27M
radioresistance and develop an innovative strategy for drug delivery to optimize the therapeutic efficacy of
radiosensitizers in the brain, potentially improving treatment outcomes for children with DMG-H3K27M.
Terms: <0-11 years old><Address><Affect><Automobile Driving><BBB crossing><BBB penetration><Biodistribution><Biology><Brachydanio rerio><Brain><Brain Cancer><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><CNS Diseases><CNS disorder><Cancer Biology><Cancer Model><Cancer Treatment><CancerModel><Cancers><Cell Body><Cell Communication and Signaling><Cell Death Induction><Cell Signaling><Cells><Cellular biology><Central Nervous System Diseases><Central Nervous System Disorders><Cessation of life><Chemicals><Child><Child Youth><Childhood><Childhood Brain Neoplasm><Childhood Brain Tumor><Children (0-21)><Clinic><Clinical><Communication><Communities><Creativeness><DIPG><DNA Damage Repair><DNA Repair><Danio rerio><Data><Death><Development><Diagnosis><Diffuse intrinsic pontine glioma><Disease><Disorder><Drug Delivery><Drug Delivery Systems><Drug Targeting><Drugs><Electroporation><Encephalon><Engineering><Ensure><Fostering><Fractionated radiotherapy><Gene Expression><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioma><Goals><Health><Heterograft><Heterologous Transplantation><Histones><Human><In Vitro><Individual><Intracellular Communication and Signaling><Intratumoral heterogeneity><Investigation><Investigators><Knowledge><Label><Link><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Mediating><Medication><Methods><Micro RNA><MicroRNAs><Microfluidic Device><Microfluidic Lab-On-A-Chip><Microfluidic Microchips><Microfluidics><Mission><Modeling><Modern Man><Mutation><Neuroglial Neoplasm><Neuroglial Tumor><Outcome><Pathway interactions><Patients><Penetrance><Pharmaceutical Preparations><Phase><Population><Postdoc><Postdoctoral Fellow><Process><Proteomics><Public Health><R-Series Research Projects><R01 Mechanism><R01 Program><Radiation><Radiation Sensitivity><Radiation Sensitizers><Radiation Tolerance><Radiation therapy><Radiation-Sensitizing Agents><Radiation-Sensitizing Drugs><Radioresistance><Radiosensitivity><Radiosensitizing Agents><Radiosensitizing Drugs><Radiotherapeutics><Radiotherapy><Radiotherapy sensitizer><Receptor Protein><Research><Research Associate><Research Grants><Research Personnel><Research Project Grants><Research Projects><Research Training><Researchers><Resistance><Role><Scientist><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Surface><Testing><Therapeutic><Training><Treatment Efficacy><Treatment outcome><Tumor Cell><Tumor-Derived><Unscheduled DNA Synthesis><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><Zebra Danio><Zebra Fish><Zebrafish><antagonism><antagonist><anti-cancer therapy><biological signal transduction><blood-brain barrier crossing><blood-brain barrier penetration><bloodbrain barrier crossing><bloodbrain barrier penetration><cancer cell><cancer microenvironment><cancer progression><cancer therapy><cancer-directed therapy><cell biology><cell type><combinatorial><creativity><delivery vector><delivery vehicle><developmental><diffuse midline glioma><driving><drug/agent><electroporative delivery><extracellular vesicles><gene electrotransfer><genome mutation><glial-derived tumor><heterogeneity in tumors><improved><inhibitor><innovate><innovation><innovative><insight><intervention efficacy><intra-tumoral heterogeneity><intratumor heterogeneity><kids><knock-down><knockdown><machine learning based model><machine learning model><malignancy><miRNA><miRNAs><microfluidic chip><multidisciplinary><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><neuroglia neoplasm><neuroglia tumor><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation><novel><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><overexpress><overexpression><pathway><pediatric><pediatric brain neoplasm><pediatric brain tumor><post-doc><post-doctoral><post-doctoral trainee><radiation resistance><radiation resistant><radiation treatment><radio resistance><radio-sensitivity><radioresistant><radiosensitive><radiosensitizer><receptor><research associates><resistance to therapy><resistant><resistant to radiation><resistant to therapy><skills><social role><standard of care><success><therapeutic efficacy><therapeutic resistance><therapy efficacy><therapy resistant><tool><treatment resistance><treatment strategy><treatment with radiation><tumor><tumor heterogeneity><tumor microenvironment><tumor progression><tumors in the brain><uptake><vesicle release><vesicular release><xeno-transplant><xeno-transplantation><xenograft transplant model><xenotransplant model><youngster><µfluidic>