Our research program has developed a novel, trimodal gene therapy-based approach for the treatment of cancer. Our approach utilizes a cytolytic, replication-competent adenovirus (Ad5-CD/TKrep) to selectively and efficiently deliver a pair of therapeutic """"""""suicide"""""""" genes to tumors. Our preclinical studies have demonstrated that the Ad5-CD/TKrep virus itself, via its cytolytic activity, has potent anti-tumor activity. The efficacy of Ad5-CD/TKrep viral therapy can be enhanced significantly by invoking two suicide gene systems (CD/5-FC and HSV-1 TK/GCV), which render malignant cells sensitive to specific pharmacological agents and importantly, sensitizes them to radiation. A major objective of Project 1 is to develop second-generation adenoviruses that may be more efficacious and less toxic than the parental Ad5-CD/TKrep virus. We will determine whether second-generation adenoviruses containing various E3 genes demonstrate greater anti-tumor activity in an immune-competent host relative to the parental Ad5-CD/TKrep virus. We will test the hypothesis that suppression of the host immune response by E3 genes will result in longer-term therapeutic gene expression and improved tumor control. Anti-tumor activity will be correlated with the duration of therapeutic gene expression in vivo and the extent, and nature, of the immune response. We will determine whether second-generation adenoviruses expressing a more catalytically active yeast CD/mutant HSV-1 TK(SR39) transgene results in better tumor control than the parental Ad5-CD/TKrep virus. We will examine the toxicity of second-generation adenoviruses in the immune-competent mouse following intraprostatic and intravenous administration. Finally, we will develop a series of second-generation adenoviruses expressing the human sodium iodide symporter (hNIS). We will test the hypothesis that expression of hNIS will enable virus-infected cells to take up (99m)TcO4- and (123)I and allowing for non-invasive monitoring of vector biodistribution and therapeutic gene expression in vivo. All of the second-generation adenoviruses developed in Project 1 will be used in the other projects of this Program.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA097012-05
Application #
7667318
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
5
Fiscal Year
2008
Total Cost
$302,888
Indirect Cost
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Freytag, Svend O; Stricker, Hans; Lu, Mei et al. (2014) Prospective randomized phase 2 trial of intensity modulated radiation therapy with or without oncolytic adenovirus-mediated cytotoxic gene therapy in intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys 89:268-76
Lu, Mei; Freytag, Svend O; Stricker, Hans et al. (2011) Adaptive seamless design for an efficacy trial of replication-competent adenovirus-mediated suicide gene therapy and radiation in newly-diagnosed prostate cancer (ReCAP Trial). Contemp Clin Trials 32:453-60
Barton, Kenneth N; Stricker, Hans; Elshaikh, Mohamed A et al. (2011) Feasibility of adenovirus-mediated hNIS gene transfer and 131I radioiodine therapy as a definitive treatment for localized prostate cancer. Mol Ther 19:1353-9
Kumar, Sanath; Freytag, Svend O; Barton, Kenneth N et al. (2010) A novel method of boron delivery using sodium iodide symporter for boron neutron capture therapy. J Radiat Res 51:621-6
Siddiqui, Farzan; Kolozsvary, Andrew; Barton, Kenneth N et al. (2009) Does hyperthermia increase adenoviral transgene expression or dissemination in tumors? Int J Hyperthermia 25:273-9
Freytag, Svend O; Stricker, Hans; Peabody, James et al. (2007) Five-year follow-up of trial of replication-competent adenovirus-mediated suicide gene therapy for treatment of prostate cancer. Mol Ther 15:636-42
Freytag, Svend O; Barton, Kenneth N; Brown, Stephen L et al. (2007) Replication-competent adenovirus-mediated suicide gene therapy with radiation in a preclinical model of pancreatic cancer. Mol Ther 15:1600-6
Brown, Stephen L; Freytag, Svend O; Barton, Kenneth N et al. (2007) Reporter gene imaging using radiographic contrast from nonradioactive iodide sequestered by the sodium-iodide symporter. Contrast Media Mol Imaging 2:240-7
Barton, Kenneth N; Freytag, Svend O; Nurushev, Teamour et al. (2007) A model for optimizing adenoviral delivery in human cancer gene therapy trials. Hum Gene Ther 18:562-72
Freytag, Svend O; Movsas, Benjamin; Aref, Ibrahim et al. (2007) Phase I trial of replication-competent adenovirus-mediated suicide gene therapy combined with IMRT for prostate cancer. Mol Ther 15:1016-23

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