Preclinical Evaluation of Serine/Threonine Kinase Inhibitors Against Prostate Cancer Metastases

摘要

This proposal studied the role of TGF Beta signaling in prostate cancer. To summarize, it is a useful target for treatment of prostate cancer bone metastases, provided that the tumor cells are responsive to the factor and show components of osteolytic lesions. TGF Beta inhibitors are not beneficial when the bone metastases phenotype is predominantly osteoblastic. Smad- independent pathways downstream of the TGF Beta receptors, such as p38 MAP kinase, do not appear to be appropriate targets for pharmacological treatment of prostate cancer bone metastases. There is no advantage to combined treatment targeting TGF Beta receptors and p38 MAP kinase. PMEPA1 may be an important target of TGF Beta in prostate cancer cells and responsible for potentiating responsiveness of tumor cells in bone to the local actions of bone-released TGF Beta. Its regulation and isoformspecific effects are complex and will be the subject of future grant proposals. TGF Beta inhibition increases bone mass systemically thru effects to stimulate differentiation of osteoblasts and inhibiting osteoclasts. The effects on osteoblasts may be via stat3 induction of Wnt ligand production.