Core B - Experimental Glioma Animal Models Core This core facility will assist each Project Leader in this Program Project Grant to test, in relevant animal models of brain tumors, preclinical safety and efficacy of various therapies designed to achieve an improved anti-glioma effect The animal models we will employ are likely to identify both toxicity and efficacy of therapeutic modalities that might be advanced to treat patients with malignant brain tumors. This core will centralize animal experimentation associated with this Program, standardizing expert surgical and animal handling techniques and minimizing chances for trivial interferences that could hamper comparative analyses. Tumor volume, tumor mass and survival statistics will be collected where appropriate. Normal and tumor tissues will be collected and submitted to each investigator or will be processed in this core for gene expression or histopathologic analyses. Project 1 will require glioma xenografts in immunocompromised mice to determine the safety and efficacy of wild-type HSV-1 engineered to target human malignant glioma cells expressing unique receptor molecules. Hybridomas expressing anti-CDI 33 will be produced in the Core to acquire single chain antibody DNA. Project 2 will evaluate the capacity of a AYI34.5 HSV engineered to express activated MEK to facilitate HSV late gene expression in human glioma xenografts in the brains of nude mice. Project 3 will examine the susceptibility of human glioma progenitor cells in human glioma xenografts to genetically engineered HSV to define virus-host cell interactions and to characterize and improve HSV-mediated oncolysis of gliomas. Project 4 will characterize virus-host interactions in brain tumor tissues from a Phase I clinical trials with M032 (human IL-12 expressing). The Core will assist with development of animal brain tumor models to test findings from these correlative studies with human glioma specimens. Bioluminescence imaging to monitor glioma growth and response to therapy will be coordinated by the Core. The Core will assist with pre-IND safety studies in HSV-sensitive New-World owl monkeys (Aotus spp.) or marmosets (Callithrix spp) conducted to define any unanticipated toxicities to primate brain The Core will coordinate with the 8.5T/9.4T Small Animal NMR Facility for all NMR imaging studies of tumor- bearing mice involved in these preclinical evaluations and will coordinate with the 4.7T nonhuman primate NMR for imaging and spectroscopic studies. Finally, the Core will continue to evaluate serially passaged human glioma xenografts as well as specific transgenic models for preclinical toxicity and efficacy analyses for each ofthe unique genetically engineered HSV developed and/or characterized by Projects 1, 2 and 3.
The EGAM Core is an essential component to the process of translating novel therapies from the laboratory to clinical application. Animal testing, performed in a highly standardized fashion by trained, skilled and experienced professionals, is a prerequisite for FDA approval to initiate-IRB approved clinical trials in humans. Moreover, our brain tumor models replicate, in most ways, the biology and physiology of high grade gliomas in patients and as such can be predictive of the likelihood of success or failure of novel therapies.
|Jackson, Joshua D; Markert, James M; Li, Li et al. (2016) STAT1 and NF-ÎºB Inhibitors Diminish Basal Interferon-Stimulated Gene Expression and Improve the Productive Infection of Oncolytic HSV in MPNST Cells. Mol Cancer Res 14:482-92|
|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|
|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|
|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:|
|Shu, Minfeng; Du, Te; Zhou, Grace et al. (2015) Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia. Proc Natl Acad Sci U S A 112:E5420-6|
|Dobbins, G Clement; Ugai, Hideyo; Curiel, David T et al. (2015) A Multi Targeting Conditionally Replicating Adenovirus Displays Enhanced Oncolysis while Maintaining Expression of Immunotherapeutic Agents. PLoS One 10:e0145272|
|Cripe, Timothy P; Chen, Chun-Yu; Denton, Nicholas L et al. (2015) Pediatric cancer gone viral. Part I: strategies for utilizing oncolytic herpes simplex virus-1 in children. Mol Ther Oncolytics 2:|
|Friedman, G K; Nan, L; Haas, M C et al. (2015) Î³â‚34.5-deleted HSV-1-expressing human cytomegalovirus IRS1 gene kills human glioblastoma cells as efficiently as wild-type HSV-1 in normoxia or hypoxia. Gene Ther 22:348-55|
|Jackson, J D; McMorris, A M; Roth, J C et al. (2014) Assessment of oncolytic HSV efficacy following increased entry-receptor expression in malignant peripheral nerve sheath tumor cell lines. Gene Ther 21:984-90|
|Roth, Justin C; Cassady, Kevin A; Cody, James J et al. (2014) Evaluation of the safety and biodistribution of M032, an attenuated herpes simplex virus type 1 expressing hIL-12, after intracerebral administration to aotus nonhuman primates. Hum Gene Ther Clin Dev 25:16-27|
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