Laboratory of Molecular Design
Targeting Prostate Cancer Gene Products for Diagnosis
Despite the great strides in diagnosis and treatment, prostate cancer (PC) affects one in every six men >60 yr old, and will kill over 30,000 US men in 2009. Early diagnosis can accelerate therapeutic intervention; improve management of PC, and save patients from morbidity and mortality. Serum prostate specific antigen (PSA) levels, transrectal ultrasonography (TRUS), and MRI (Magnetic Resonance imaging) the routine tests, suffer from serious limitations and require invasive biopsies for histologic confirmation. In 2009, ~750,000 prostate biopsies will be performed, >2/3 of which had benign pathology. A compelling need exists for noninvasive, early and accurate methods to a) localize primary PC, b) detect recurrent disease, and c) image metastatic lesions. VPAC1 receptor is overexpressed in all PC cells. Activation of oncogene CCND1.b isoform leads to expression of mutant cyclin D1b protein, which stimulates prostate cell proliferation at the onset of PC, an AR-dependent stage. Elevation of VPAC1 and CCND1.b expression present themselves prior to elevation of PSA and before cell morphology is altered. Cyclin D1b protein promotes PC cell proliferation until their ultimate progression to AR-independence induced by androgen blockade. CCND1 (a/b) knockdown slows proliferation of some cancer cells. We have successfully initiated the use of Tc-99m or Cu-64 labeled VPAC1 receptor-specific peptide constructs and mRNA-specific peptide nucleic acid (PNA) constructs to image disease-specific oncogene products in mice bearing a variety of human cancer xenografts and in patients with breast cancers. We hypothesize that quantitative PET imaging of elevated VPAC1 receptor with specific Cu-64 probes will diagnose PC early and contribute to its management. We further hypothesize that PET imaging of CCND1.b mRNA with Cu-64-labeled PNA will quantitate mRNA copies/cell, enable tumor imaging, and monitor therapeutic effectiveness. In order to validate our hypotheses, we propose 1) to evaluate a Cu-64 peptide specific for VPAC1, to diagnose PC; 2) to synthesize, characterize, and to evaluate PNA constructs specific for CCND1.b mRNA for imaging; 3) to determine the imaging efficacy of Cu-64-peptide and Cu-64 PNA constructs specific for CCND1.b mRNA in athymic nude mice bearing human PC, and in TRAMP transgenic mice that develop spontaneous PC. Gene product imaging results will be compared with sequence controls and F-18-FDG scans. PC histology will serve as the gold standard. These molecular imaging approaches to diagnose, PC are novel and unique. Promising results will allow us to translate this technology from bench to bedside.
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