The median survival for patients with malignant glioma remains less than 12 months despite aggressive multimodal therapy. Chemoradiation is now a standard of care in the treatment of malignant gliomas involving the use of concurrent temozolomide (TMZ), an oral DNA alkylating agent, with ionizing radiation (IR) followed by IR alone. Enhancement of the effects of IR and chemotherapy may further increase patient survival and quality of life. We have shown that the herpes simplex virus (HSV) protein, ICPO, can inhibit the repair of DNA double-strand breaks (DSBs) and enhance apoptosis of human glioblastoma multiforme (GBM) cells after irradiation. In addition, we have preliminary data showing a significant antitumor response in a mouse intracranial glioma model after intracerebral convection-enhanced delivery (CED) of the ICPO-producing HSV-1 mutant, d106, in combination with whole-brain irradiation (10 Gy) or TMZ treatment. Chemo/radiotherapy-activated gene therapy is a developing paradigm that that can allow for targeted treatment of malignant gliomas. We propose the development and use of new HSV replication-defective viruses that contain chemoinducible/radioinducible/hypoxiainducible promoters that selectively express the HSV immediate-early (IE) protein, ICPO, with temozolomide, IR, and/or hypoxic conditions. First, to produce the new viruses, the native ICPO promoter of the ICPO-producing HSV mutant, d106, will be substituted with promoters responsive to IR, TMZ, and/or hypoxia. Second, optimal delivery of HSV mutant viruses will be determined in vivo by CED. Third, transcriptional targeting of ICPO by IR, TMZ, and hypoxia will be assessed in vitro and in vivo with a mouse glioma model. A proposal for the development of the Pi's expertise in the fields of molecular biology, cancer biology, viral gene therapy, and human cancer modeling is also presented. Completion of these goals will serve to transition the PI from a mentored to independent clinician scientist.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS053454-05
Application #
7885270
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fountain, Jane W
Project Start
2006-07-21
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$125,281
Indirect Cost
Name
Emory University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Platt, Simon; Nduom, Edjah; Kent, Marc et al. (2012) Canine model of convection-enhanced delivery of cetuximab-conjugated iron-oxide nanoparticles monitored with magnetic resonance imaging. Clin Neurosurg 59:107-13
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Hadjipanayis, Costas G; Machaidze, Revaz; Kaluzova, Milota et al. (2010) EGFRvIII antibody-conjugated iron oxide nanoparticles for magnetic resonance imaging-guided convection-enhanced delivery and targeted therapy of glioblastoma. Cancer Res 70:6303-12
Tzitzios, Vassilios; Basina, Georgia; Bakandritsos, Aristides et al. (2010) Immobilization of magnetic iron oxide nanoparticles on laponite discs - an easy way to biocompatible ferrofluids and ferrogels. J Mater Chem 20:5418-5428
Hadjipanayis, Costas G; Schuette, Albert J; Boulis, Nicholas et al. (2010) Full scope of options. Neurosurgery 67:197-203; discussion 203-4

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