The bone marrow of the axial skeleton is the preferred site of metastases in the large majority of patients with prostate cancer. The striking selectivity has been viewed as an example of site-specific cell-cell interactions that are essential to prostate cancer progression. Despite the obvious clinical relevance, little is known about the mechanisms that control prostate cancer metastasis. In addition, there are no effective strategies for targeting therapeutic agents for the treatment of metastatic prostate cancer. Here, we propose to select peptides that home to bone marrow and to prostate cancer bone metastasis. Phage peptides libraries will be screened in vivo and ex-vivo. In vivo phage display technology has been developed and used successfully to target several organs and tumors and generate probes with selective homing capabilities. We will select and characterize bone marrow and prostate cancer bone metastases- homing peptides; such peptides will be used to target therapies against metastatic prostate cancer and in understanding the mechanisms that control prostate cancer metastasis. We will then identify the receptors for the peptide ligands using biochemical and genetic methods. Finally, we will test the effects of targeted therapies in prostate cancer bone metastases. Two classes of receptors known to be up-regulated in angiogenic vasculature will be targeted, metalloproteases and aminopeptidases. Extensive previous work shows that these receptors are not accessible in the vasculature of normal organs and that the inhibition of such proteases leads to tumor regression. Novel therapeutic strategies to inhibit prostate cancer metastatic spread to bone marrow will derive from this work. Peptides that target prostate cancer bone metastases will be developed as delivery tools and will likely enhance effectiveness of existing therapies.
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