Adenovirus vectors are among the most popular vehicles for gene therapy protocols currently used to attack cancers, because of their use of genetic manipulation, their ability to be prepared at high titres and their ability to efficiently transfer genetic material into appropriate target cells. However, adenovirus gene therapy vectors have several targeting disadvantages; (i) they infect non-tumor cells that express the Coxsakie and Adenovirus Receptor, CAR, thus diverting vectors from the target cell and (ii) infect target tumor cells via cell-specific targeting mechanisms based either on a biochemical manipulation or genetic alterations of the virus. We developed two adenoviruses, Ad-D2R and Ad-HSV1-tk, that delivery PET reporter genes, whose expression can be monitored with positron- labeled probes and demonstrated their efficacy in transferring these reporter genes to murine liver. We will now use these PET reporter viruses and PET reporter probes to investigate the efficacy of bi-specific antibodies (Bi-Ab) and molecular conjugates to redirect adenovirus gene therapy vectors to tumor cells. Specifically, we will investigate the ability of (i) a Bi-Ab directed to the therapy vectors to tumor cells. Specifically, we will investigate the ability of (i) a Bi-Ab directed to the [epidermal growth factor (EGF) receptor][adenovirus knob protein] and (ii) a [soluble CAR][EGF] complex to redirect Ad-D2R and Ad-HSV 1-tk to xenografts of A431 epidermoid carcinoma cells (which express 2-3x106 EGF receptors) xenografted to nude mice subcutaneously, in the lung, in the liver and in the bone marrow. In collaboration with David Curiel at the U. of Alabama we will identify, from phage display libraries, peptides and single chain antibody fragments that react from EGFR, incorporate these peptides into both the fiber protein HI loop and the hexon hypervariable 5 region of HSV-1 tk expressing adenoviruses, and ablate the CAR binding site. Targeting of these viruses for A431 xenografts will be examined by microPET. Only by using PET receptor gene/reporter probe technology can we obtain the resolution, quantitation and non- invasive characteristics necessary to monitor the distribution and gene transfer capability of these biochemically and genetically retargeted adenovirus gene therapy vectors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA086306-03
Application #
6587316
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2002-05-01
Project End
2003-04-30
Budget Start
Budget End
Support Year
3
Fiscal Year
2002
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Waldmann, Christopher M; Gomez, Adrian; Marchis, Phillip et al. (2018) An Automated Multidose Synthesis of the Potentiometric PET Probe 4-[18F]Fluorobenzyl-Triphenylphosphonium ([18F]FBnTP). Mol Imaging Biol 20:205-212
Graham, Nicholas A; Minasyan, Aspram; Lomova, Anastasia et al. (2017) Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. Mol Syst Biol 13:914
Balandeh, Mehrdad; Waldmann, Christopher; Shirazi, Daniela et al. (2017) Electrochemical Fluorination and Radiofluorination of Methyl(phenylthio)acetate Using Tetrabutylammonium Fluoride (TBAF). J Electrochem Soc 164:G99-G103
Waldmann, Christopher M; Lebedev, Artem; Allison, Nathaniel et al. (2017) An automated synthesizer for electrochemical 18F-fluorination of organic compounds. Appl Radiat Isot 127:245-252
Lee, Jason T; Zhang, Hanwen; Moroz, Maxim A et al. (2017) Comparative Analysis of Human Nucleoside Kinase-Based Reporter Systems for PET Imaging. Mol Imaging Biol 19:100-108
Barrio, Martin; Czernin, Johannes; Yeh, Michael W et al. (2016) The incidence of thyroid cancer in focal hypermetabolic thyroid lesions: an 18F-FDG PET/CT study in more than 6000 patients. Nucl Med Commun 37:1290-1296
Tavaré, Richard; Escuin-Ordinas, Helena; Mok, Stephen et al. (2016) An Effective Immuno-PET Imaging Method to Monitor CD8-Dependent Responses to Immunotherapy. Cancer Res 76:73-82
Kirkby, Nicholas S; Chan, Melissa V; Zaiss, Anne K et al. (2016) Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-?B and NFAT transcriptional pathways. Proc Natl Acad Sci U S A 113:434-9
Kim, Woosuk; Le, Thuc M; Wei, Liu et al. (2016) [18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity. Proc Natl Acad Sci U S A 113:4027-32
Clark, Peter M; Mai, Wilson X; Cloughesy, Timothy F et al. (2016) Emerging Approaches for Targeting Metabolic Vulnerabilities in Malignant Glioma. Curr Neurol Neurosci Rep 16:17

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