Metastasis is the main cause of prostate cancer mortality. The support of prostate cancer SPORE Developmental Program in the past two years has enabled us to investigate the contribution of lymphangiogenesis 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 cell dissemination to regional lymph nodes. Moreover, the lymphatic dissemination process also greatly impacts metastasis to distal organs, such as lung and liver. Hence, our current working hypothesis suggests that lymphatic circulation is a preferred route of dissemination and that regional lymph nodes provide a reservoir from which subsequent dissemination to distal sites occurs. This proposal will investigate this hypothesis further. In particular, we will examine in detail the connection between lymphangiogenic pathways and metastasis in prostate cancer patients, focusing our molecular and histological analyses on the patients with node 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 and diagnostic imaging of nodal metastasis. We will investigate therapeutic effects of blockading the lymphangiogenic tyrosine kinase receptor by specific VEGFR3 antibody, and Sorafenib, a multi-kinase inhibitor known to target both VEGFR3. Molecular imaging technologies will be applied to monitor the impact of these interventions on the metastatic process. We will also evaluate the ability of a prostate-specific imaging adenoviral vector to specifically detect nodal metastases in preclinical models. In addition, we will develop and assess potential circulating surrogate markers for the lymphangiogenic pathways. The lack of such markers has halted progress in anti-metastatic treatment. The prostate cancer SPORE program at University 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 tissue samples from the patients to analyze the molecular activity of Sorafenib against the VEGFR3 pathway and tumor lymphangiogenesis axis. The myriad of approaches taken in this proposal is directed towards improving the clinical management of metastasis stage of prostate cancer in the future.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA092131-09
Application #
8094356
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
9
Fiscal Year
2010
Total Cost
$239,188
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Miller, Eric T; Salmasi, Amirali; Reiter, Robert E (2018) Anatomic and Molecular Imaging in Prostate Cancer. Cold Spring Harb Perspect Med 8:
Navarro, H├ęctor I; Goldstein, Andrew S (2018) HoxB13 mediates AR-V7 activity in prostate cancer. Proc Natl Acad Sci U S A 115:6528-6529
Mitra, Mithun; Ho, Linda D; Coller, Hilary A (2018) An In Vitro Model of Cellular Quiescence in Primary Human Dermal Fibroblasts. Methods Mol Biol 1686:27-47
Li, Jiayun; Speier, William; Ho, King Chung et al. (2018) An EM-based semi-supervised deep learning approach for semantic segmentation of histopathological images from radical prostatectomies. Comput Med Imaging Graph 69:125-133
Kang, Jung J; Reiter, Robert E; Kummer, Nicolas et al. (2018) Wrong to be Right: Margin Laterality is an Independent Predictor of Biochemical Failure After Radical Prostatectomy. Am J Clin Oncol 41:1-5
Lee, Ha Neul; Mitra, Mithun; Bosompra, Oye et al. (2018) RECK isoforms have opposing effects on cell migration. Mol Biol Cell 29:1825-1838
Aggarwal, Rahul; Huang, Jiaoti; Alumkal, Joshi J et al. (2018) Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study. J Clin Oncol 36:2492-2503
Cheng, Larry C; Li, Zhen; Graeber, Thomas G et al. (2018) Phosphopeptide Enrichment Coupled with Label-free Quantitative Mass Spectrometry to Investigate the Phosphoproteome in Prostate Cancer. J Vis Exp :
Park, Jung Wook; Lee, John K; Sheu, Katherine M et al. (2018) Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage. Science 362:91-95
Tan, Nelly; Shen, Luyao; Khoshnoodi, Pooria et al. (2018) Pathological and 3 Tesla Volumetric Magnetic Resonance Imaging Predictors of Biochemical Recurrence after Robotic Assisted Radical Prostatectomy: Correlation with Whole Mount Histopathology. J Urol 199:1218-1223

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