This PPG renewal involves investigators from the University of Southern California participating in a multidisciplinary and highly interactive research effort on understanding the basic mechanisms involved in gene delivery in order to develop gene therapy approaches for the treatment of cancer. The investigators are drawn from both basic science and clinical departments. The Program consists of five research Projects and two Core resources. The theme of this Program is to apply concepts and techniques developed in molecular genetics, molecular biology, tumor biology, basic immunology and clinical immunology to illuminate poorly understood mechanisms involved in the delivery and expression of genes by retroviral vectors. Dr. W. French Anderson is engineering the ecotropic murine leukemia virus envelope protein to bind to specific cell surface receptors and to thereby direct the vectors to specific target cells. Dr. Nori Kasahara will place replication of retroviruses under the control of a cellular transcriptional promoter thus limiting replication to cells that can activate the promoter. Dr. Donald Kohn will study gene expression from retroviral and lentiviral vectors after gene transfer into HSC. He will analyze mechanisms of augmented expression from retroviral vectors produced by removal, mutagenesis or insertion of defined DNA segments. Drs. Amy Lee and Gunther Dennert will test directly in retroviral vectors the efficacy of the glucose-starvation inducible GRP78 promoter regulatory elements, alone or in combination with the hypoxic response element, to drive targeted and long-term expression of therapeutic genes in mammary carcinoma models in vivo. Dr. Robertson Parkman will establish that the transplantation of positively selected HSC transduced with lentivirus vectors can result in the lymphohematopoietic reconstitution of myeloablative recipients. The two Core resources include administration and viral vector development and these are integrated and interdependent. Finally, the Program is integrated in the University research community and in particular with the USC Gene Therapy Program, a partnership between the Norris Comprehensive Cancer Center/Institute for Genetic Medicine Joint Gene Therapy Program and the Gene Therapy Program of Childrens' Hospital Los Angeles.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA059318-10
Application #
6712075
Study Section
Subcommittee G - Education (NCI)
Program Officer
Xie, Heng
Project Start
1992-09-30
Project End
2006-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
10
Fiscal Year
2004
Total Cost
$1,683,635
Indirect Cost
Name
University of Southern California
Department
Biochemistry
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Perez, Omar D; Logg, Christopher R; Hiraoka, Kei et al. (2012) Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression. Mol Ther 20:1689-98
Christodoulopoulos, Ilias; Droniou-Bonzom, Magali E; Oldenburg, Jill E et al. (2010) Vpu-dependent block to incorporation of GaLV Env into lentiviral vectors. Retrovirology 7:4
Epand, Raquel F; Zhang, Yan-Liang; Mirzabekov, Tajib et al. (2008) Membrane activity of an amphiphilic alpha-helical membrane-proximal cytoplasmic domain of the MoMuLV envelope glycoprotein. Exp Mol Pathol 84:9-17
Rozenberg-Adler, Yanina; Conner, John; Aguilar-Carreno, Hector et al. (2008) Membrane-proximal cytoplasmic domain of Moloney murine leukemia virus envelope tail facilitates fusion. Exp Mol Pathol 84:18-30
Logg, Christopher R; Baranick, Brian T; Lemp, Nathan A et al. (2007) Adaptive evolution of a tagged chimeric gammaretrovirus: identification of novel cis-acting elements that modulate splicing. J Mol Biol 369:1214-29
Hiraoka, Kei; Kimura, Takahiro; Logg, Christopher R et al. (2007) Therapeutic efficacy of replication-competent retrovirus vector-mediated suicide gene therapy in a multifocal colorectal cancer metastasis model. Cancer Res 67:5345-53
Weber, Erin L; Cannon, Paula M (2007) Promoter choice for retroviral vectors: transcriptional strength versus trans-activation potential. Hum Gene Ther 18:849-60
Kikuchi, Eiji; Menendez, Silvia; Ozu, Choichiro et al. (2007) Highly efficient gene delivery for bladder cancers by intravesically administered replication-competent retroviral vectors. Clin Cancer Res 13:4511-8
Hsu, Faye Yuan-yi; Zhao, Yi; Anderson, W French et al. (2007) Downregulation of NPM-ALK by siRNA causes anaplastic large cell lymphoma cell growth inhibition and augments the anti cancer effects of chemotherapy in vitro. Cancer Invest 25:240-8
Kikuchi, E; Menendez, S; Ozu, C et al. (2007) Delivery of replication-competent retrovirus expressing Escherichia coli purine nucleoside phosphorylase increases the metabolism of the prodrug, fludarabine phosphate and suppresses the growth of bladder tumor xenografts. Cancer Gene Ther 14:279-86

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