TRANSCRIPTIONAL CONTROL OF THE EGF RECEPTOR GENE

ABNORMALITIES OF THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) APPEAR TO BE ASSOCIATED WITH A VARIETY OF PROLIFERATIVE DISEASES. IN HUMAN CARCINOMA BIOPSY SPECIMENS, OVEREXPRESSION OF EGFR IS FREQUENTLY OBSERVED TO OCCUR IN THE ABSENCE OF GENE AMPLIFICATION. IN PSORIATIC EPIDERMIS, AUTOCRINE STIMULATION BY TGF-ALPHA LEADS TO INAPPROPRIATE ACTIVATION OF EGFR. THE ULTIMATE GOAL OF THE PROJECT IS TO IDENTIFY LEAD COMPOUNDS WHICH CAN SPECIFICALLY DOWN-REGULATE EXPRESSION OF THE EGFR GENE. ONCOGENE SCIENCE HAS DEVELOPED A UNIQUE ROBOTIC TECHNOLOGY WHICH CAN IDENTIFY COMPOUNDS THAT ACT AS SPECIFIC MODULATORS OF GENE TRANSCRIPTION. THIS CELL-BASED SCREEN IS CAPABLE OF ANALYZING MORE THAN 3,000 CHEMICAL COMPOUNDS PER WEEK AGAINST MULTIPLE GENES TO GAUGE A COMPOUND'S EFFICACY IN SPECIFICALLY MODULATING TRANSCRIPTION OF A PARTICULAR GENE OF INTEREST. IN PHASE I, WE WILL CONSTRUCT VARIOUS EGFR PROMOTER/REPORTER VECTORS, FOLLOWED BY TRANSFECTIONS INTO APPROPRIATE CELLS TO CONFIRM THE HYPOTHESIS THAT EGFR OVEREXPRESSION IN MANY TUMOR SAMPLES RESULTS FROM ABNORMAL GENE TRANSCRIPTION. IN PHASE II, WE WILL USE THE STABLY-TRANSFECTED CELL CLONES TO IDENTIFY SPECIFIC INHIBITORS OF EGFR TRANSCRIPTION.