title: Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts.
abstract: Dose-escalated radiation therapy for localized prostate cancer (PCa) has a clear therapeutic benefit; however, escalated doses may also increase injury to noncancerous tissues. Radiosensitizing agents can improve ionizing radiation (IR) potency, but without targeted delivery, these agents will also sensitize surrounding normal tissues. Here we describe the development of prostate-targeted RNAi agents that selectively sensitized prostate-specific membrane antigen-positive (PSMA-positive) cells to IR. siRNA library screens identified DNA-activated protein kinase, catalytic polypeptide (DNAPK) as an ideal radiosensitization target. DNAPK shRNAs, delivered by PSMA-targeting RNA aptamers, selectively reduced DNAPK in PCa cells, xenografts, and human prostate tissues. Aptamer-targeted DNAPK shRNAs, combined with IR, dramatically and specifically enhanced PSMA-positive tumor response to IR. These findings support aptamer-shRNA chimeras as selective sensitizing agents for the improved treatment of high-risk localized PCa.
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Ni
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Judit
authors.initials: J
authors.lastname: Ribas
authors.forename: Wasim H
authors.initials: WH
authors.lastname: Chowdhury
authors.forename: Mark
authors.initials: M
authors.lastname: Castanares
authors.forename: Zhewei
authors.initials: Z
authors.lastname: Zhang
authors.forename: Marikki
authors.initials: M
authors.lastname: Laiho
authors.forename: Theodore L
authors.initials: TL
authors.lastname: DeWeese
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Lupold
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000532:radiotherapy*; D000818:Animals; D000954:Antigens, Surface / Q000032:analysis*; D052157:Aptamers, Nucleotide / Q000008:administration & dosage*; D002460:Cell Line; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors*; D043425:Glutamate Carboxypeptidase II / Q000032:analysis*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000954:Antigens, Surface; D052157:Aptamers, Nucleotide; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II