Urinary aHGF, IGFBP3 and OPN as diagnostic and prognostic biomarkers for prostate cancer.

AIM: Serum PSA screening for prostate cancer (PCa) is controversial. Here, we identify three urinary biomarkers - aHGF, IGFBP3 and OPN - for PCa screening and prognostication. METHODS: Urinary aHGF, OPN and IGFBP3 from healthy men (n = 19) and men with localized (n = 65) and metastatic (n = 36) PCa were quantified via ELISA. Mann-Whitney nonparametric t-test and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analyses were used to analyze associations. RESULTS: Mean aHGF and IGFBP3 levels were significantly elevated in PCa patients versus controls (p = 0.0006 and p = 0.0012, respectively), and the area under the curve of the receiver operating characteristic curve (indicator of diagnostic accuracy) for aHGF and IGFBP3 was 0.75 and 0.74, respectively. OPN levels were significantly higher in metastatic groups (p = 0.0060) versus localized and controls (area under the curve = 0.68). CONCLUSION: Urinary aHGF and IGFBP3 exhibit the capacity for diagnostic discrimination for PCa, whereas OPN may indicate presence of metastatic disease.

Urine analysis and protein networking identify met as a marker of metastatic prostate cancer.

PURPOSE: Metastatic prostate cancer is a major cause of death of men in the United States. Expression of met, a receptor tyrosine kinase, has been associated with progression of prostate cancer. EXPERIMENTAL DESIGN: To investigate met as a biomarker of disease progression, urinary met was evaluated via ELISA in men with localized (n = 75) and metastatic (n = 81) prostate cancer. Boxplot analysis was used to compare the distribution of met values between each group. We estimated a receiver operating characteristic curve and the associated area under the curve to summarize the diagnostic accuracy of met for distinguishing between localized and metastatic disease. Protein-protein interaction networking via yeast two-hybrid technology supplemented by Ingenuity Pathway Analysis and Human Interactome was used to elucidate proteins and pathways related to met that may contribute to progression of disease. RESULTS: Met distribution was significantly different between the metastatic group and the group with localized prostate cancer and people with no evidence of cancer (P < 0.0001). The area under the curve for localized and metastatic disease was 0.90, with a 95% confidence interval of 0.84 to 0.95. Yeast two-hybrid technology, Ingenuity Pathway Analysis, and Human Interactome identified 89 proteins that interact with met, of which 40 have previously been associated with metastatic prostate cancer. CONCLUSION: Urinary met may provide a noninvasive biomarker indicative of metastatic prostate cancer and may be a central regulator of multiple pathways involved in prostate cancer progression.

Phase I clinical trial of oral 2-methoxyestradiol, an antiangiogenic and apoptotic agent, in patients with solid tumors.

PURPOSE: To determine the maximum-tolerated dose (MTD) and toxicity profile of the novel anticancer agent, 2-methoxyestradiol (2ME2) administered orally, in patients with solid tumors. MATERIALS AND METHODS: Twenty patients with refractory solid tumors were enrolled. 2ME2 was given orally starting at 400 mg bid with dose escalation until 3000 mg bid. Tumor biopsies were taken before and after starting the drug to assess for microvessel density by CD 31 and cell proliferation by Ki67 immunohistochemistry. Serial plasma samples collected up to 50 hours after first single oral dose for characterization of pharmacokinetics, were analyzed using liquid chromatography tandem mass-spectrometry. RESULTS: Eleven men and nine women received 2ME2 at dose levels of 400 mg bid (n = 3), 800 mg bid (n = 3), 1600 mg bid (n = 6), 2200 mg bid (n = 5) and 3000 mg bid (n = 3). There were no dose limiting toxicities, therefore the MTD was not defined. There was one episode of grade 4 angioedema in the 1600 mg bid dose level 38 days into 2ME2 treatment. Other toxicities were mild to moderate. A patient with clear cell carcinoma of the ovary had a partial response at 1600 mg bid dose level lasting over three years. CONCLUSION: MTD for 2ME2 was not reached at dose of 3000 mg bid. The trial was closed due to extremely low plasma concentrations of 2ME2 relative to the doses administered. 2ME2 treatment had no effect on microvessel density (CD31 immunostaining) and cell proliferation (Ki-67 immunostaining). A new formulation of 2ME2 with improved bioavailability is currently being developed.