Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer death for men in the United States. Prostate tumor cells express high levels of the IGF-I receptor (IGF-IR) and because bone marrow is rich in the ligands, IGF-I and IGF-II, it has been proposed that a paracrine loop exists between osteoblasts and prostate tumor cells that favors bone marrow metastases. Once prostate cancer has metastasized to bone marrow the disease is incurable. Anti-sense RNA was used in animal studies to abolish IGF- IR expression in tumor cell lines, there was a loss of the tranformed pheotype, tumorigenesis, and metastatic ability. However, anti-sense RNA strategies pose significant drug delivery problems. Recent data suggest the IGF-IR mRNA is post-transcriptionally regulated. Symphony has developed technology that exploits RNA/RNA binding protein (RBP) interactions as a target for modulating protein expression. We propose to map sites in the IGF-IR mRNA that interact with RBP's using in vitro RNA mobility shift assays and cell- based luciferase reporter gene assays of chimeric RNA. Once we have identified these sites in the IGF-IR mRNA that interact with RBP's using in vitro RNA mobility shift assays and cell-based luciferase reporter gene assays of chimeric RNA. Once we have identified these sites, these sequences will beused as targets in a Phase II study to identify small molecules that bind the RNA to modulate protein expression. POTENTIAL COMMERCIAL APPLICATIONS The potential commercial application of the proposed research is the development of therapetic agents for the treatment of prostate cancer. These agents will target IGF-I receptor expression through a novel mechanism of action and may be applicable to other forms of cancer. Additional success with the SCRIBE technology will also attract licensing agreements with other pharmaceutical companies.
