It is likely that specific miRNAs, a class of non-protein-encoding, small RNAs may be potential therapeutic targets for controlling metastases. Accordingly, the hypotheses to be tested in this proposal are that: (i) metastasis-associated miRNAs can be identified via a comparison of metastatic and non-metastatic human prostate cancer models; and (ii) some of the metastasis-associated miRNAs and/or their target genes will provide potential therapeutic targets for metastatic prostate cancer. To test this hypothesis, we will combine and synergize the unique expertise and extensive resources of the four independent PIs. A highly novel approach will be used to compare the miRNA profiles of paired metastatic and non-metastatic models derived from the same patient by applying a new generation of sequencing technology to initially identify and then functionally validate miRNAs linked to metastases. While the metastasis-linked miRNAs may themselves serve as therapeutic targets in that regard, identification of the specific genes that they directly regulate may reveal more specific gene markers and targets, particularly since most miRNAs regulate a wide variety of genes. For this purpose, a very new and innovative experimental strategy for screening for these miRNA-regulated genes is proposed which takes advantage of our experience with viral-based systems and complementary synergies. If we are to have any major impact on current survival rates, then new alternative treatment strategies need to be developed to target molecular events responsible for the development of prostate cancer metastases. The outcomes from this research should provide new therapeutic targets for controlling prostate cancer metastases in patients with advanced or recurrent disease. It is likely that clinical candidates for these purposes will be available after the 5-year term of this application.