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Principal Investigator: Deepak Bhere
Organization: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
Fiscal Year: 2024
Award: $248,997
Funding agency: National Cancer Institute
ABSTRACT
Each year upwards of 14,000 patients are diagnosed with Glioblastoma (GBM), the most malignant form of
primary brain tumor. Surgical resection followed by radio and chemotherapies are the treatment options for
GBM, but patients generally succumb to the disease. MicroRNAs (miR) are emerging as key regulators of
cellular differentiation and proliferation; have been implicated in the etiology of a variety of cancers, including
GBM. Our exciting preliminary studies show great promise for exosomes shed from induced pluripotent stem
cell derived - neural stem cells (iNSC) expressing miR-124 to target brain tumors. In the mentored (K99)
phase of this study, I will evaluate the immune effects mediated by miR-124 delivered locally into the tumor
bed via encapsulated neural stem cells following tumor debulking. We hypothesize that miR-124 modulation by
exosomes enriched in miR-124 from NSC, when delivered into the tumor resection cavity will target tumor cell
proliferation and enhance T-cell mediated immune clearance of GBM cells. Once these effects are validated, in
the R00 phase of the award, the potential synergy between the modulation of miR-7 and miR-124, which target
AKT and STAT3 respectively will be studied to develop a sECM encapsulated iNSC delivered miR-7/ miR-124
therapeutic approach to target resected GBM. In order to ensure safety of iNSC implantation, the herpes simplex
virus – thymidine kinase suicide gene system will be incorporated. The efficacy of iNSC-miR-7/miR-124/HSV-TK
will be evaluated in mouse models of GBM resection. We hypothesize that dual modulation of miR-124 and miR-
7 will target the AKT-STAT3 signaling that is critical to tumor cell growth and together with the activation of host
immune system medicated tumor clearance will present therapeutic benefit. Upon validation, this microRNA
based therapeutic strategies will pave path to much needed novel treatments to target GBM.
Terms: <21+ years old><AKT><Abscission><Address><Adjuvant Chemotherapy><Adjuvant Drug Therapy><Adult><Adult Human><After Care><After-Treatment><Aftercare><Akt protein><Award><Beds><Blood - brain barrier anatomy><Blood-Brain Barrier><Brain><Brain Cancer><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><CNS Diseases><CNS disorder><Cancers><Causality><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Growth in Number><Cell Line><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell-Extracellular Matrix><CellLine><Cells><Cellular Expansion><Cellular Growth><Cellular Proliferation><Central Nervous System Diseases><Central Nervous System Disorders><Clinical><Data><Debulking><Deoxypyrimidine Kinase><Deoxythymidine Kinase><Development><Diagnosis><Disease><Disorder><Drug Delivery><Drug Delivery Systems><ECM><EGF Receptor><EGFR><ERBB Protein><Encapsulated><Encephalon><Engineering><Ensure><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Etiology><Excision><Extirpation><Extracellular Matrix><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Ganciclovir><Gancyclovir><Generalized Growth><Glioblastoma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Growth><HER1><HSV><Hemato-Encephalic Barrier><Herpes Simplex Virus><Herpes labialis Virus><Immune><Immune Cell Activation><Immune response><Immune system><Immunes><Immunity><Immunological response><Implant><In Vitro><Intracellular Communication and Signaling><Intrasurgical Resection Cavity><Kinetics><Knowledge><Malignant><Malignant - descriptor><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Mediating><Mentors><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modeling><Molecular><Murine><Mus><Neural Stem Cell><Nordeoxyguanosine><Operative Procedures><Operative Surgical Procedures><PET><PET Scan><PET imaging><PETSCAN><PETT><Pathway interactions><Patients><Phase><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Primary Brain Neoplasms><Primary Brain Tumors><Progenitor Cells><Prognosis><Protein Kinase B><Proto-Oncogene Proteins c-akt><Publishing><RAC-PK protein><Rad.-PET><Radiation therapy><Radiotherapeutics><Radiotherapy><Regimen><Removal><Resected><Resection Cavity><Role><STAT3><STAT3 gene><Safety><Signal Transduction><Signal Transduction Systems><Signaling><Simplexvirus><Small RNA><Strains Cell Lines><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Surgically-Created Cystic Resection Cavity><Surgically-Created Resection Cavity><Survival Analyses><Survival Analysis><System><T-Cell Activation><T-Cells><T-Lymphocyte><TGF-alpha Receptor><Testing><Therapeutic><Therapeutic Agents><Thymidine Kinase><Time><Tissue Growth><Transforming Growth Factor alpha Receptor><Treatment Efficacy><Tumor Burden><Tumor Cell><Tumor Debulking><Tumor Load><Tumor Volume><Up-Regulation><Upregulation><Urogastrone Receptor><Validation><activate T cells><adulthood><biological signal transduction><bloodbrain barrier><c-akt protein><c-erbB-1><c-erbB-1 Protein><cancer microenvironment><causation><cell growth><cellular differentiation><chemotherapy><clinical care><clinical translation><clinically translatable><cultured cell line><cytoreductive surgery><develop therapy><developmental><disease causation><effective therapy><effective treatment><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><exosome><flow cytophotometry><fluorescence imaging><fluorescent imaging><glioblastoma multiforme><host response><iPS><iPSC><iPSCs><image guidance><image guided><imaging agent><immune activation><immune clearance><immune elimination><immune system response><immunoresponse><implantation><in vivo><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><intervention development><intervention efficacy><malignancy><miR therapy><miR-based therapeutic><miR-based therapy><miRNA><miRNA therapy><miRNA-based therapeutic><miRNA-based therapy><miRNAs><microRNA therapy><microRNA-based therapeutic><microRNA-based therapy><migration><mouse model><murine model><neoplasm/cancer><neoplastic cell><nerve stem cell><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neuron progenitors><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuroprogenitor><novel><ontogeny><pathway><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><post treatment><promoter><promotor><proto-oncogene protein RAC><proto-oncogene protein akt><proto-oncogene protein c-erbB-1><rac protein kinase><radiation treatment><related to A and C-protein><resection><response><restoration><social role><spongioblastoma multiforme><stem cells><success><suicide gene><surgery><surgical cytoreduction><synergism><therapeutic efficacy><therapeutic miRNA><therapeutic miRs><therapeutic microRNA><therapy development><therapy efficacy><thymus derived lymphocyte><treatment development><treatment strategy><treatment with radiation><tumor><tumor cytoreduction><tumor microenvironment><tumors in the brain><validations>