Project 1 has had two major objectives. The first was to enhance effectiveness of candidate therapeutic viruses constructed by deletion of specific genes. These viruses are more effective in treatment that combines virus administration to the tumor and radiation. Nevertheless, the effectiveness of combined therapy is tumor genotype-dependent. In the past 5 years, we have collaborated with Project 2 to (a) identify the molecular basis for enhancement of attenuated viruses by ionizing radiation (IR) and (b) identify a cellular gene (MEK) whose product, when used properly in conjunction with IR, could overcome the restriction to attenuated virus replication imposed by tumor genotypes. The results of these studies are described in the Progress Report for Project 2. Our second objective was to construct viruses that can only infect cancer cells but not normal cells. In essence we ablated the ability of HSV-1 to attach to heparin sulfate proteoglycans and to enter cells by way of its natural protein receptors, HveA and nectin 1. Thus, the engineered virus R5141 infects cells solely via the IL13 a2 receptor while R5181 enters cells via the urokinase plasminogen activator receptor. Our findings have significantly contributed to understanding the biology and biochemistry of glycoprotein (g) D. Our new objectives are as follows:
AIM 1 will develop methods for production of clinical grade targeted viruses. Since targeted viruses must be produced in noncancerous cells that stably express the novel receptor(s), we propose several ways in which we can produce clinical grade viruses. The objective of AIM 2 is to develop more effective viruses for therapy of GBM with AY34.5 mutant viruses. Therapeutic viruses currently in clinical trials extend survival time in a small fraction of treated patients in a tumor genotype dependent manner. We have constructed a virus in which the constitutively active MEK gene is driven by an IR inducible promoter (R2660). In preliminary studies R2660 plus IR blocked growth of a tumor resistant to virus or IR alone. The safety features of this and other mutant viruses will be studied. The objective of AIM 3 is to render the viruses targeting specific receptors on cell surfaces more effective. We have established proof of principle but do not consider the current generation optimal. We have identified specific shortcomings and ways to improve these viruses The objective of AIM 4 is based on the novel observation that a component of the amino-terminal domain of the urokinase plasminogen activator receptor interacts with the carboxyl-terminus of the gD ectodomain. The amino terminus of urokinase plasminogen activator contains a Kringle domain with affinity for lysines. Thus, we will determine whether the Kringle domain of human plasminogen can be used to target gD and by extension, target HSV-1 to its ligand, the glucose regulatory protein 78.
Project 1 is a component of a Program Project Grant designed to cure or at least effectively prolong quality of life of patients with malignant gliomas. At this point in time the proof of principle has been established at both basic and clinical levels. The task confronting Project 1 is to design, construct and test the next generation of therapeutic viruses characterized by enhanced therapeutic profile and to develop methods for their production in GMP facilities. Validation ofthe novel viruses will be done in collaboration with Projects 2 and 3 and, ultimately, with Project 4.
|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|
|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; 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|
|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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