Measles virus exerts its cytopathic effect by cell-cell fusion which eventually leads to cell death. We have cloned the cDNA for the measles F and H fusogenic membrane glycoproteins into eukaryotic expression vectors and have shown significant cytotoxicity through induction of cell-cell fusion in different human tumor cell lines including A431 (epithelial carcinoma), C170 (colon cancer), HeLa (cervical cancer), TE671 (rhabdomyosarcoma), and the glioma cell lines U87 and U118. In addition, we have shown significantly higher bystander effects as compared to the herpes simplex thymidine kinase (HSV-tk) system. This proposal utilizes the fusogenic membrane proteins F and H of the measles virus to develop a clinician investigator's career in gene transfer/gene therapy. The applicant proposes to: 1) Investigate the use of fusogenic measles virus proteins F and H as novel therapeutic transgenes using the U87 and U118 glioma models. Gliomas were selected because they are highly lethal tumors despite the therapeutic use of surgery, radiation therapy, and chemotherapy. They also offer the further advantage of their limited metastatic potential that makes them appropriate targets for intratumoral gene transfer/gene therapy. We plan to a) construct retroviral vectors encoding the F and H transgenes, b) compare the developed vectors with the gold standard of cytotoxicity which is HSV-tk producing retroviral vectors in both glioma cell lines and tumor xenografts, and c) target vectors to the tumor environment by exploiting the over-expression of matrix metalloproteinases in gliomas. The long-term goal is to introduce this novel transgene system into clinical trials as a new therapeutic alternative. 2) Develop expertise to pursue an independent clinician scientist career within the area of gene transfer/gene therapy. In addition to the interaction with the mentor and co-mentors, this will be achieved through attending Mayo Graduate School courses and major scientific meetings, such as the American Association for Cancer Research and the American Society of Gene Therapy meetings.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA084388-04
Application #
6633594
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2000-05-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
4
Fiscal Year
2003
Total Cost
$114,588
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Galanis, Evanthia; Buckner, Jan C; Maurer, Matthew J et al. (2006) Validation of neuroradiologic response assessment in gliomas: measurement by RECIST, two-dimensional, computer-assisted tumor area, and computer-assisted tumor volume methods. Neuro Oncol 8:156-65
Galanis, E; Okuno, S H; Nascimento, A G et al. (2005) Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas. Gene Ther 12:437-45
Allen, Cory; McDonald, Cari; Giannini, Caterina et al. (2004) Adenoviral vectors expressing fusogenic membrane glycoproteins activated via matrix metalloproteinase cleavable linkers have significant antitumor potential in the gene therapy of gliomas. J Gene Med 6:1216-27
Galanis, Evanthia; Burch, Patrick A; Richardson, Ronald L et al. (2004) Intratumoral administration of a 1,2-dimyristyloxypropyl-3- dimethylhydroxyethyl ammonium bromide/dioleoylphosphatidylethanolamine formulation of the human interleukin-2 gene in the treatment of metastatic renal cell carcinoma. Cancer 101:2557-66
Phuong, Loi K; Allen, Cory; Peng, Kah-Whye et al. (2003) Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme. Cancer Res 63:2462-9
Johnson, K J; Peng, K-W; Allen, C et al. (2003) Targeting the cytotoxicity of fusogenic membrane glycoproteins in gliomas through protease-substrate interaction. Gene Ther 10:725-32
Galanis, E; Bateman, A; Johnson, K et al. (2001) Use of viral fusogenic membrane glycoproteins as novel therapeutic transgenes in gliomas. Hum Gene Ther 12:811-21
Galanis, E; Russell, S (2001) Cancer gene therapy clinical trials: lessons for the future. Br J Cancer 85:1432-6
Daniels, G A; Galanis, E (2001) Immunotherapy of renal cell carcinoma by intratumoral administration of an IL-2 cDNA/DMRIE/DOPE lipid complex. Curr Opin Mol Ther 3:70-6
Galanis, E; Vile, R; Russell, S J (2001) Delivery systems intended for in vivo gene therapy of cancer: targeting and replication competent viral vectors. Crit Rev Oncol Hematol 38:177-92