The long-range objectives of the Core are to utilize pertinent mouse models of Glioblastoma Multiforme (GBM) to study the roles of Extracellular Vesicles (EVs) in influencing the tumor microenvironment and therapeutic responses to standard of care (SoC) treatment, gene mediated cytotoxic immunotherapy (GMCI) and immune checkpoint inhibitors therapies. The goals of the Core are to provide technical, intellectual and scientific support to all three Projects of this P01 application. The Core has been providing valuable services to this PPG for the last 4 years and will continue to be a central component of the overall goals of the Program by delivering an appropriate platform to conduct pre-clinical studies that will educate and expedite clinical trials. We will utilize validated EGFR- and PDGFR?-based GBM GEM models and well-characterized PDX models and their Glioma Stem Cells (GSCs) to address the needs of the Projects. Animal transfer protocols between the different institutions are in place. We will adapt and refine these models to meet the evolving requirements of each individual Project, including the generation and characterization of new strains of mice for the detection of fluorescently tagged microglial cells. The Core is perfectly positioned to bring technology and knowhow to bear on the science of this P01.
The Specific Aims are:
Aim 1) To evaluate and implement GMCI therapy in the context of standard of care treatments in EGFR- and PDGFR?-based GEM and PDX models.
Aim 2) To utilize EGFR- and PDGFR?-based pre-clinical GEM models to evaluate the functions of EVs in modulating immune checkpoint inhibitors immunotherapy.
Aim 3) To design, generate and characterize genetically engineered transgenic strains of mice with fluorescently labeled microglia for the study of GBM tumor-derived EV on microglial function.
Glioblastoma multiforme, like all other tumors, reside within an environment that heavily influences their growth behavior and resistance to therapies. The communication between tumor and microenvironment cells is extensive and is still being deciphered mechanistically. A recently discovered modality of such communication is through the exchange of information between tumor cells and normal cells through small vesicles that contain biological materials. These Extracellular Vesicles (EVs) have been shown to sway normal cells into supporting tumor growth. The goals of this project are to provide mouse models of glioblastoma to study the effects of EVs on the outcome of therapies in a pre-clinical setting. Success in this project will undoubtedly expedite the design and creation of future clinical trials.
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