Bone cancers have grave clinical consequences and affect the lives of hundreds of thousands of patients in the United States each year. Novel strategies for treating these malignancies are desperately needed to advance treatment and embark on prevention of bone cancer. The pathophysiology of virtually all bone cancers is intimately linked to bone cancer-induced osteoclast formation. The long range goal of our laboratory is to understand the interaction between bone cancer and bone cells and to use this knowledge as the basis for developing novel methods for treating and preventing bone cancer. The objective of this proposal is to use knowledge of osteoclast (OCL) precursors and osteoclast lineage-specific gene promoters to develop an ex vivo gene delivery system that kills bone cancer cells. The central hypothesis of this proposal is that an osteoclast precursor-based, prodrug gene delivery system will permit killing of bone-residing cancers. The prodrug system selected is the cytosine deaminase/5 flourocytosine system. This hypothesis is based on Preliminary Studies, indicating that 1) OCL precursors home to sites of bone cancer, 2) OCL precursors can be purified and transduced to express selected genes, 3) customized retroviral vectors provide osteoclast lineage-specific expression of marker genes, and 4) a cytosine deaminase gene delivery system kills bone cancer cell in vitro. To evaluate the central hypothesis, the following aims will be pursued: 1. Demonstrate that transplanted osteoclast precursors will home to sites of bone cancer. 2. Identify the retroviral vector which achieves maximal and specific expression of a marker gene in osteoclast lineage cells. 3. Demonstrate that transplanted osteoclast precursors will express a maker gene specifically at sites of bone cancer. 4. Determine if an osteoclast precursor-mediated cytosine deaminase gene delivery system permits killing of bone cancer cells. Proving our central hypothesis will represent an extraordinary advance towards development of new cancer therapies and will shift the focus of bone cancer treatments from palliation to cure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047302-04
Application #
6752849
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Sharrock, William J
Project Start
2001-08-03
Project End
2005-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$367,609
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Orthopedics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Ramnaraine, Margaret L; Mathews, Wendy E; Clohisy, Denis R (2012) Lentivirus transduction of human osteoclast precursor cells and differentiation into functional osteoclasts. Bone 50:97-103
Ramnaraine, Margaret L; Mathews, Wendy E; Donohue, James M et al. (2006) Osteoclasts direct bystander killing of bone cancer. Cancer Res 66:10929-35
Selski, Daniel J; Clohisy, Denis R (2006) A customized retroviral vector confers marker gene expression in osteoclast lineage cells. J Cell Biochem 97:641-50
Goblirsch, Michael; Lynch, Christine; Mathews, Wendy et al. (2005) Radiation treatment decreases bone cancer pain through direct effect on tumor cells. Radiat Res 164:400-8
Pan, Weihong; Mathews, Wendy; Donohue, J Michael et al. (2005) Analysis of distinct tartrate-resistant acid phosphatase promoter regions in transgenic mice. J Biol Chem 280:4888-93
Clohisy, D R; Mantyh, P W (2004) Bone cancer pain and the role of RANKL/OPG. J Musculoskelet Neuronal Interact 4:293-300
Ramnaraine, Margaret; Pan, Weihong; Goblirsch, Michael et al. (2003) Direct and bystander killing of sarcomas by novel cytosine deaminase fusion gene. Cancer Res 63:6847-54