The utility and limitations of the TRAMP model system for studying the effects of hedgehog targeted therapy in prostate cancer
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Advanced prostate cancer has a very poor prognosis and no curative therapies. Understanding of the hedgehog (Hh) signaling pathway, a potential target in prostate cancer may lead to an effective therapy. We have explored the use of the TRAMP mouse model of prostate cancer to evaluate Hh signaling in prostate cancer. We have found that two compounds from spinach, spinacetin and patuletin, will inhibit cancer cell growth and Hh signaling in vitro. A spinach diet fed to TRAMP had a slight inhibition on cancer incidence, but not Hh signaling. To validation the TRAMP model for Hh studies, we treated TRAMP mice with cyclopamine, the first identified inhibitor of the Hh pathway. Cyclopamine treatment resulted in non-significant reductions of key Hh target genes and prostate size. The TRAMP cell line isograft model was used to test disulfiram, a drug approved in the mid-20th century for treatment of alcoholism. Although disulfiram proved to be a potent inhibitor of Hh signaling in vitro, with 100 nM inhibiting cancer cell growth and reducing Hh pathway activity, an in vivo study did not show tumor or Hh inhibition. While studies have shown the Hh pathway to be present in TRAMP mice and in cell lines established from tumors removed from TRAMP mice, our studies imply that this pathway may not be a key driver of prostate cancer growth in TRAMP mice. Further studies may bring additional understanding of the Hh pathway in the TRAMP model.
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