The Experimental Glioma Tissue (EGT) Core Facility will provide a wide range of histologic, immunologic and in vivo animal testing services to the second and third Projects directly and to the first Project indirectly to assist in critical in vivo evaluation of genetically engineered herpes simplex viruses (HSV) for the treatment of human malignant gliomas. The objective will be to provide correlative evidence of both safety (lack of neurovirulence) and efficacy (anti-tumor activity) of in vitro selected genetically engineered HSV in normal or severe combined immune deficiency (scid) mice bearing syngeneic or xenogeneic (human) glioma grafts. We will evaluate virulence of selected HSV injected into normal or stab-wounded brain tissue of mice and, for highly selected viruses, subhuman primates (Aotus monkeys) by (a) clinical monitoring (b) microscopic examination of injected brain tissue for morphologic pathology; (c) immunohistochemical and immunofluorescent studies using a wide variety of immunologic reagents as described in the second and third Projects. The EGT core facility will also be responsible for developing and validating a new intracranial glioma model that can be used to test combined therapy involving extracranial radiation to activate expression of HSV-transduced genes intratumorally via x-irradiation promoters. Efficacy will be determined using prolongation of survival and regression of intracranial gliomas of mouse or human origin in immunocompetent (C57BL/6) or immunocompromised (C.B-17 scid)mice. The core will assist in assessment of tumorigenic potential and viral susceptibility of in situ recovered human malignant glioma cells that have survived HSV mutant virus exposure as described in the second Project. The goal will be to improve viral production and/or delivery to achieve a more efficacious result. In summary, the EGT Core will provide assistance to investigators in the second and third Projects to define the anti-tumor effects produced in vivo by selected HSV mutants by (a) immunohistochemical/immunofluorescent identification of viral, tumor cell and host immune related inflammatory cell components with engrafted murine and human gliomas, (b) functional examination of intratumoral immune-related cells, and (c) distribution of induced and transduced cytokine expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA071933-04
Application #
6324642
Study Section
Project Start
2000-07-01
Project End
2001-06-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
4
Fiscal Year
2000
Total Cost
$215,218
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Friedman, Gregory K; Bernstock, Joshua D; Chen, Dongquan et al. (2018) Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression. Sci Rep 8:13930
Waters, Alicia M; Johnston, James M; Reddy, Alyssa T et al. (2017) Rationale and Design of a Phase 1 Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors. Hum Gene Ther Clin Dev 28:7-16
Ring, Eric K; Markert, James M; Gillespie, G Yancey et al. (2017) Checkpoint Proteins in Pediatric Brain and Extracranial Solid Tumors: Opportunities for Immunotherapy. Clin Cancer Res 23:342-350
Foreman, Paul M; Friedman, Gregory K; Cassady, Kevin A et al. (2017) Oncolytic Virotherapy for the Treatment of Malignant Glioma. Neurotherapeutics 14:333-344
Ring, Eric K; Li, Rong; Moore, Blake P et al. (2017) Newly Characterized Murine Undifferentiated Sarcoma Models Sensitive to Virotherapy with Oncolytic HSV-1 M002. Mol Ther Oncolytics 7:27-36
Friedman, Gregory K; Moore, Blake P; Nan, Li et al. (2016) Pediatric medulloblastoma xenografts including molecular subgroup 3 and CD133+ and CD15+ cells are sensitive to killing by oncolytic herpes simplex viruses. Neuro Oncol 18:227-35
McFarland, Braden C; Marks, Margaret P; Rowse, Amber L et al. (2016) Loss of SOCS3 in myeloid cells prolongs survival in a syngeneic model of glioma. Oncotarget 7:20621-35
Jackson, Joshua D; Markert, James M; Li, Li et al. (2016) STAT1 and NF-?B Inhibitors Diminish Basal Interferon-Stimulated Gene Expression and Improve the Productive Infection of Oncolytic HSV in MPNST Cells. Mol Cancer Res 14:482-92
Patel, Daxa M; Foreman, Paul M; Nabors, L Burt et al. (2016) Design of a Phase I Clinical Trial to Evaluate M032, a Genetically Engineered HSV-1 Expressing IL-12, in Patients with Recurrent/Progressive Glioblastoma Multiforme, Anaplastic Astrocytoma, or Gliosarcoma. Hum Gene Ther Clin Dev 27:69-78
Friedman, Gregory K; Beierle, Elizabeth A; Gillespie, George Yancey et al. (2015) Pediatric cancer gone viral. Part II: potential clinical application of oncolytic herpes simplex virus-1 in children. Mol Ther Oncolytics 2:

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