The progression of prostate cancer to a metastatic disease involves the accumulation of metastasis-promoting genes and inactivation of metastasis-suppressing genes. We have focused on the discovery of such molecules and have discovered four chemokines that uniquely predict biochemical recurrence of prostate cancer following prostatectomy. We have shown that the expression of one of the chemokines is upregulated and two downregulated in patients that develop recurrent disease following prostate surgery after diagnosis of prostate cancer. Preliminary data indicate that in 180 prostate cancer patients the combination of the use of these chemokines in conjunction with three other clinical determinants commonly used (Gleason score, pre-operative PSA, and surgical margins) provides a far superior prediction for biochemical recurrence of prostate cancer following prostatectomy than conventional methods used currently where pre-operative PSA, Gleason score, and cancer status in the lymph node, seminal vesicle, and surgical margins are employed. More importantly, the measurement of the chemokines in prostate tissue provides significant predictive value to existing algorithms of calculating recurrence of prostate cancer. As recurrent disease following prostatectomy is indicative of cancer cells that have escaped into the local or distant sites of the body, these chemokines are potentially important players in the metastatic progression of prostate cancer.

At present, little is known of the function or regulation of these chemokines in prostate cancer. With the rationale that for a biomarker to be clinically meaningful biologic relevance needs to be shown, this proposal tests the hypothesis that chemokine biomarkers identified to predict biochemical prostate cancer recurrence following prostatectomy regulate metastatic progression of the cancer. The goal of this proposal is to characterize its potential as a biomarker in predicting prostate cancer recurrence through further characterization of their ability to impact metastatic potential of human prostate cancer cells in culture and in unique xenograft mouse models. We will examine the direct effect of the chemokines on the cancer cells as well as their role in the immune response to the cancer. We will analyze the effects of altered chemokine expression on cell growth, adhesion, and migration. In vivo studies will assess the role of chemokine expression in tumor progression and metastasis.

Prostate cancer is a common disease that is generally incurable if detected after distant metastasis has occurred. Clinical decisions about how to treat individual prostate cancer patients rely on information about disease stage (whether organ-confined or metastatic) and histological grade. In summary, we have developed an effective paradigm for identifying and characterizing proteins whose expression is altered in prostate cancer patients that differentiate those that develop recurrent disease. We want to be able to apply this knowledge to determine biologic function for these biomarkers for early adjuvant therapy to prevent disease progression as well as provide preclinical evidence of targets for therapy of patients with high risk of metastatic prostate cancer.