MP34-12 TARGETING IGF-BP2 AND 5 WITH THE BISPECIFIC ANTISENSE OLIGODEOXYNUCLEOTIDE OGX-225 IN CHEMORESISTANT BLADDER CANCER (2014)

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 2014MP34-12 TARGETING IGF-BP2 AND 5 WITH THE BISPECIFIC ANTISENSE OLIGODEOXYNUCLEOTIDE OGX-225 IN CHEMORESISTANT BLADDER CANCER Wolfgang Jäger, Tetsutaro Hayashi, Joseph Ischia, Claudia Janßen, Shannon Awrey, Ladan Fazli, Martin Gleave, and Peter Black Wolfgang JägerWolfgang Jäger More articles by this author , Tetsutaro HayashiTetsutaro Hayashi More articles by this author , Joseph IschiaJoseph Ischia More articles by this author , Claudia JanßenClaudia Janßen More articles by this author , Shannon AwreyShannon Awrey More articles by this author , Ladan FazliLadan Fazli More articles by this author , Martin GleaveMartin Gleave More articles by this author , and Peter BlackPeter Black More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1025AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Patients presenting with muscle-invasive bladder cancer (MIBC) are at high risk for developing systemic disease, and more than half will succumb to their cancer despite optimal multimodal therapy that includes cytotoxic chemotherapy. While chemotherapy often induces tumor regression, this response is rarely durable as the tumor is repopulated with chemoresistant cells. Chemoresistance arises from a multitude of possible mechanisms which include insulin-like growth factor (IGF) signaling. Here we report on the targeting of insulin-like growth factor-binding protein (IGFBP) -2 and IGFBP-5 with a bispecific antisense oligodeoxynucleotide (ASO; designated OGX-225), as a novel strategy to treat chemoresistant bladder cancer. METHODS Immunohistochemistry was performed on a tissue microarray (TMA) derived from 104 patients tumors. Acquired chemoresistance was induced in the three cell lines by exposure to gradually increasing drug doses: 253-JBV (10mM cisplatin), T24 (10mM cisplatin) and UM-UC3 (10mM gemcitabine). The expression of IGFBP-2 and -5 in parenteral and resistant cell lines was assessed by quantitative PCR and Western blot. Effects of OGX-225 treatment on IGFBP-2 and IGFBP-5 expression, cell growth (crystal violet), and apoptosis (caspase 3, cell cycle analysis) were evaluated. Effects of combining OGX-225 with chemotherapy were analyzed, with particular focus on potential re-sensitization of resistant cells. The effect of OGX-225 as a single agent and in combination with cytotoxic chemotherapy was measured in resistant UM-UC3 (gemcitabine) and T24 (cisplatin) orthopotic xenografts. RESULTS High expression of IGFBP-2 in cystectomy specimens was associated with adverse clinical outcome. IGFBP-2 was significantly overexpressed in chemoresistant compared to parenteral cell lines at the mRNA and protein levels. OGX-225 induced potent dose-dependent, sequence-specific knockdown of IGFBP-2 and -5 in parenteral and resistant cell lines. This treatment decreased cell viability through induction of apoptosis. Combination treatment showed a re-sensitization of resistant cell lines to cisplatin (253-JBV, T24) and gemcitabine (UM-UC3). Compared to control ASO, OGX-225 also inhibited growth of chemoresistant orthotopic xenografts and re-sensitized them to cytotoxic chemotherapy. CONCLUSIONS Our data indicate that IGF signaling is involved in the acquisition of chemoresistance in MIBC, and that inhibiting IGFBP-2 and IGFBP-5 with OGX-225, a novel bispecific ASO, was able to overcome this chemoresistance. This provides pre-clinical proof-of-principle for a novel treatment strategy for patients with bladder cancer. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e366 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Wolfgang Jäger More articles by this author Tetsutaro Hayashi More articles by this author Joseph Ischia More articles by this author Claudia Janßen More articles by this author Shannon Awrey More articles by this author Ladan Fazli More articles by this author Martin Gleave More articles by this author Peter Black More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...