Metastasis is the main cause of prostate cancer mortality. The support of prostate cancer SPOREDevelopmental Program in the past two years has enabled us to investigate the contribution oflymphangiogenesis to prostate cancer metastasis. We discovered that elevated pro-lymphangiogenic factor(VEGF-C) in the prostate tumors induces the growth of lymphatic vessels, which in turn facilitates tumor celldissemination to regional lymph nodes. Moreover, the lymphatic dissemination process also greatly impactsmetastasis to distal organs, such as lung and liver. Hence, our current working hypothesis suggests thatlymphatic circulation is a preferred route of dissemination and that regional lymph nodes provide a reservoirfrom which subsequent dissemination to distal sites occurs. This proposal will investigate this hypothesisfurther. In particular, we will examine in detail the connection between lymphangiogenic pathways andmetastasis in prostate cancer patients, focusing our molecular and histological analyses on the patients withnode positive and recurrent disease. Using many relevant preclinical models developed at our institution,our efforts will be directed towards addressing two areas of great need, i.e. therapeutic intervention anddiagnostic imaging of nodal metastasis. We will investigate therapeutic effects of blockading thelymphangiogenic tyrosine kinase receptor by specific VEGFR3 antibody, and Sorafenib, a multi-kinaseinhibitor known to target both VEGFR3. Molecular imaging technologies will be applied to monitor the impactof these interventions on the metastatic process. We will also evaluate the ability of a prostate-specificimaging adenoviral vector to specifically detect nodal metastases in preclinical models. In addition, we willdevelop and assess potential circulating surrogate markers for the lymphangiogenic pathways. The lack ofsuch markers has halted progress in anti-metastatic treatment. The prostate cancer SPORE program atUniversity of Washington is initiating a phase II neoadjuvant clinical trial of Sorafenib in patients with high-risk localized prostate cancer. In a collaborative effort with this study, we will obtain blood and tissuesamples from the patients to analyze the molecular activity of Sorafenib against the VEGFR3 pathway andtumor lymphangiogenesis axis. The myriad of approaches taken in this proposal is directed towardsimproving the clinical management of metastasis stage of prostate cancer in the future.
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