POSTTRANSCRIPTIONAL CONTROL OF IGF I RECEPTOR EXPRESSION

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. $ = TOTAL AWARD AMTS & NOT LIMITED TO PORTION OF PROJECT RELATED TO SUBJECT OF SEARCH SUBPROJECT $ = TOTAL AWARD AMOUNT DIVIDED BY NUMBER OF SUBPROJECTS SOURCE: CRISP FORMAT F FY 97 LAST UPDATE 04-07-98 1QUERY 1536 ID SEARCH 06/01/98 PAGE 201 --PROJECT NUMBER......1 R43 CA75838-01 INVESTIGATOR NAME/ADDRESS FY 97 GIORDANO, ANTHONY IRG/INTRAMURAL UNIT..ZRG2 BEARSDEN BIO, INC. AWARD AMOUNT......... $100,000 600 SWEDESFORD RD FRAZER, PA 19355 PERFORMING ORGANIZATION: BEARSDEN BIO, INC. TITLE MOLECULAR CLONING OF UNIQUE CYTOKINES & PROTOONCOGENES ABSTRACT: Cytokines and protooncogenes are critical modulators of cellular function, viability, differentiation and communication. As such, cytokines are now being used in the treatment of many diseases including cancer, autoimmunity, anemia and renal failure. It is likely that in the near future drugs capable of interfering with protooncogenes will also find clinical use. The long term objective of this project is to identify new cytokines and protooncogenes by a novel affinity chromatographic technique. Using this process, we have constructed several cDNA libraries which are substantially enriched for cytokine and protooncogene cDNAs. Thirty-five percent of randomly screened cDNAs from this library code for known cytokines or protooncogenes while an equal percentage are unique without homology to known human mRNAs. The aims of this Phase I project are to 1). identify all novel cDNAs within the library by partial nucleotide sequencing and database search and 2). clone the corresponding full-length cDNAs from tissue specific cDNA libraries. If we are successful, we will apply for Phase 2 funds to construct new libraries from additional cell and tissue sources, characterize the functionality of our novel cytokines and protooncogenes and begin the commercialization process for these important new molecules with established pharmaceutical companies.