The overall goal of this project is to assess systemic delivery of angiostatic genes as a means of inhibiting tumor antiogenesis. The specific objectives are to compare two methods of systemic gene delivery and two angiostatic genes for their ability to inhibit angiogenesis and tumor growth, using both experimental tumor models (mice) and hypothesis that sustained systemic production of an angiostatic factor by in vivo gene delivery can inhibit angiogenesis in animals with established tumors. The rationale for this proposal is that sustained in vivo expression of angiostatic genes by systemic non-viral gene delivery techniques may be a more effective and practical approach to angiogenesis inhibition than repeated parenteral injections of purified proteins. Two endogenous angiostatic factors (endostatin and angiostatin), that have both demonstrated impressive antitumor activity in vivo, will be evaluated. The objective of this proposal will be accomplished using three specific aims: (1) compare the effectiveness of intravenous versus intramuscular gene delivery in murine tumor models; (2) determine optimal DNA doses for intravenous and intramuscular gene delivery in dogs; and (3) assess antiangiogenic activity and tumor responses to systemic endostatin gene therapy in dogs with malignant melanoma. The results of these studies, which include assessment of angiogenic markers and treatment outcomes in a pertinent large animal tumor model, will provide a clinically realistic evaluation of this novel approach to inhibition to tumor angiogenesis. Such an approach may be broadly applicable to therapeutic modulation of aniogenesis in general, using genes or combinations of genes that either inhibit or stimulate angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA086224-03
Application #
6548020
Study Section
Special Emphasis Panel (ZCA1-SRRB-3 (J1))
Program Officer
Goldman, Stephen
Project Start
2000-08-11
Project End
2005-07-31
Budget Start
2002-01-01
Budget End
2002-07-31
Support Year
3
Fiscal Year
2001
Total Cost
$163,125
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Other Clinical Sciences
Type
Schools of Veterinary Medicine
DUNS #
112617480
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
U'Ren, Lance; Guth, Amanda; Kamstock, Debra et al. (2010) Type I interferons inhibit the generation of tumor-associated macrophages. Cancer Immunol Immunother 59:587-98
Elmslie, R E; Glawe, P; Dow, S W (2008) Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas. J Vet Intern Med 22:1373-9
Dow, Steven (2008) Liposome-nucleic acid immunotherapeutics. Expert Opin Drug Deliv 5:11-24
Lana, Susan; U'ren, Lance; Plaza, Susan et al. (2007) Continuous low-dose oral chemotherapy for adjuvant therapy of splenic hemangiosarcoma in dogs. J Vet Intern Med 21:764-9
Biller, B J; Elmslie, R E; Burnett, R C et al. (2007) Use of FoxP3 expression to identify regulatory T cells in healthy dogs and dogs with cancer. Vet Immunol Immunopathol 116:69-78
Kamstock, Debra; Elmslie, Robyn; Thamm, Douglas et al. (2007) Evaluation of a xenogeneic VEGF vaccine in dogs with soft tissue sarcoma. Cancer Immunol Immunother 56:1299-309
U'Ren, Lance W; Biller, Barbara J; Elmslie, Robyn E et al. (2007) Evaluation of a novel tumor vaccine in dogs with hemangiosarcoma. J Vet Intern Med 21:113-20
Zaks, Karen; Jordan, Michael; Guth, Amanda et al. (2006) Efficient immunization and cross-priming by vaccine adjuvants containing TLR3 or TLR9 agonists complexed to cationic liposomes. J Immunol 176:7335-45
Walter, Claudia U; Biller, Barbara J; Lana, Susan E et al. (2006) Effects of chemotherapy on immune responses in dogs with cancer. J Vet Intern Med 20:342-7
McMahan, Rachel H; McWilliams, Jennifer A; Jordan, Kimberly R et al. (2006) Relating TCR-peptide-MHC affinity to immunogenicity for the design of tumor vaccines. J Clin Invest 116:2543-51

Showing the most recent 10 out of 15 publications