Abstract

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. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08NS053454-01A1
Application #
7145786
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fountain, Jane W
Project Start
2006-07-21
Project End
2007-06-30
Budget Start
2006-07-21
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$168,842
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Costas G (2015) Radiosensitivity enhancement of radioresistant glioblastoma by epidermal growth factor receptor antibody-conjugated iron-oxide nanoparticles. J Neurooncol 124:13-22
Kaluzova, Milota; Bouras, Alexandros; Machaidze, Revaz et al. (2015) Targeted therapy of glioblastoma stem-like cells and tumor non-stem cells using cetuximab-conjugated iron-oxide nanoparticles. Oncotarget 6:8788-806
Wang, Quan; Wei, Feng; Lv, Guoyue et al. (2013) The association of TP53 mutations with the resistance of colorectal carcinoma to the insulin-like growth factor-1 receptor inhibitor picropodophyllin. BMC Cancer 13:521
Nduom, Edjah K; Bouras, Alexandros; Kaluzova, Milota et al. (2012) Nanotechnology applications for glioblastoma. Neurosurg Clin N Am 23:439-49
Wankhede, Mamta; Bouras, Alexandros; Kaluzova, Milota et al. (2012) Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy. Expert Rev Clin Pharmacol 5:173-86
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
Hadjipanayis, Costas G; Jiang, Huabei; Roberts, David W et al. (2011) Current and future clinical applications for optical imaging of cancer: from intraoperative surgical guidance to cancer screening. Semin Oncol 38:109-18
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

Showing the most recent 10 out of 16 publications