MP29-14 TARGETING HYALURONIC ACID FAMILY BIOMARKERS FOR TREATMENT OF RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research II1 Apr 2014MP29-14 TARGETING HYALURONIC ACID FAMILY BIOMARKERS FOR TREATMENT OF RENAL CELL CARCINOMA Nicolas Ortiz, Michael Garcia-Roig, Travis Yates, Murugesan Manoharan, and Vinata Lokeshwar Nicolas OrtizNicolas Ortiz More articles by this author , Michael Garcia-RoigMichael Garcia-Roig More articles by this author , Travis YatesTravis Yates More articles by this author , Murugesan ManoharanMurugesan Manoharan More articles by this author , and Vinata LokeshwarVinata Lokeshwar More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.756AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Up to 25% of patients with renal cell carcinoma (RCC) have metastasis at initial diagnosis. Current targeted therapies (e.g., Sorafenib) are not curative and the 5-year survival of these patients is <10%. Molecular determinants of RCC growth and metastasis may be accurate prognostic markers for metastasis and could be targeted for therapy. We evaluated the expression of 3 genes (and their splice variants) as prognostic indicators. We also tested the therapeutic efficacy of the combination of hymecromone (HC), a non-toxic, orally bioavailable hyaluronic acid (HA) synthesis inhibitor and Sorafenib (SF). METHODS Tumor specimens were collected from RCC patients undergoing nephrectomy (n=81; T1, 40; T2+, 41; Fuhrman Grade 1, 5; Grade 2, 32; Grade 3, 25; Grade 4, 19). Nine patients developed metastasis within 15 months. Tissue-RNA was subjected to Q-PCR for HA family of markers (i.e. HAS3, CD44, RHAMM). mRNA levels were correlated with metastasis by logistic regression. Effect of HC, SF and HC+SF on cell proliferation, cell cycle and apoptosis was examined in RCC cells (Caki-1, 786-O, ACHN, 769-P) by cell counting, flow cytometry and Cell Death ELISA. Boyden chamber was used for motility assay. Effect on cell cycle, apoptosis, and HA-receptor levels was evaluated by immunoblotting and Q-PCR. RESULTS The mRNA levels of HAS3, CD44 and RHAMM were 3 to 7-fold elevated in RCC tissues from patients who developed metastasis when compared to those who did not develop metastasis during the follow up period. In univariate analysis age, grade, stage, CD44 and RHAMM levels significantly correlated with metastasis. In multivariate analysis, CD44 (< 0.0001), HAS3 (P=0.03) and RHAMM (P< 0.0001) significantly correlated with metastasis. Among the three markers, RHAMM had the highest accuracy (89.5%) in predicting metastasis. Combination of HC (15-30-μg/ml) and SF (1.6 to 3.2 μg/ml), at non-cytotoxic doses caused 60-90% inhibition in proliferation, motility and invasion after 48-72 h treatment. Only the combination induced apoptosis (3-4-fold). HC+SF combination down regulated CD44 and RHAMM mRNA levels by 2- and 68-fold, respectively and inhibited HA synthesis. In Caki-1xenograft, oral treatment with combination caused 100% inhibition of tumor growth. CONCLUSIONS HAS3, CD44 and RHAMM expression in RCC tissues is potentially an independent prognostic indicator for metastasis. HC+SF combination may be a potentially effective treatment for metastatic RCC. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e310 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Nicolas Ortiz More articles by this author Michael Garcia-Roig More articles by this author Travis Yates More articles by this author Murugesan Manoharan More articles by this author Vinata Lokeshwar More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...