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.
Xiaohua Ni, Yonggang Zhang, Judit Ribas, Wasim H. Chowdhury, Mark Castanares, Zhewei Zhang, Marikki Laiho, Theodore L. DeWeese, Shawn E. Lupold
Title and authors | Publication | Year |
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Systemic Administration and Targeted Radiosensitization via Chemically Synthetic Aptamer-siRNA Chimeras in Human Tumor Xenografts
X Ni, Y Zhang, K Zennami, M Castanares, A Mukherjee, RR Raval, H Zhou, TL DeWeese, SE Lupold |
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Nucleic Acid Aptamer-Guided Cancer Therapeutics and Diagnostics: the Next Generation of Cancer Medicine
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Smart functional nucleic acid chimeras: Enabling tissue specific RNA targeting therapy
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Characterization of a novel metastatic prostate cancer cell line of LNCaP origin: Characterization of JHU-LNCaP-SM
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The Prostate | 2015 |
Targeting Transcriptional Regulators of CD8+ T Cell Dysfunction to Boost Anti-Tumor Immunity
K Waugh, S Leach, J Slansky |
Human vaccines | 2015 |
Methods in Molecular Biology
WH Thiel, KW Thiel, KS Flenker, T Bair, AJ Dupuy, JO McNamara, FJ Miller, PH Giangrande |
Methods in molecular biology (Clifton, N.J.) | 2015 |
A Highlight of Recent Advances in Aptamer Technology and Its Application
H Sun, Y Zu |
Molecules (Basel, Switzerland) | 2015 |
A cell-based high-throughput screening assay for radiation susceptibility using automated cell counting
J Hodzic, I Dingjan, MJ Maas, IH van der Meulen-Muileman, RX de Menezes, S Heukelom, M Verheij, WR Gerritsen, AA Geldof, B Triest, VW van Beusechem |
Radiation Oncology | 2015 |
A functional screen identifies miRNAs that inhibit DNA repair and sensitize prostate cancer cells to ionizing radiation
K Hatano, B Kumar, Y Zhang, JB Coulter, M Hedayati, B Mears, X Ni, TA Kudrolli, WH Chowdhury, R Rodriguez, TL DeWeese, SE Lupold |
Nucleic Acids Research | 2015 |
Oligonucleotide therapies – the past and the present
KE Lundin, OI Gissberg, E SMITH |
Human Gene Therapy | 2015 |
Aptamer–Drug Conjugates
G Zhu, G Niu, X Chen |
Bioconjugate Chemistry | 2015 |
Identifying high-affinity aptamer ligands with defined cross-reactivity using high-throughput guided systematic evolution of ligands by exponential enrichment
A Levay, R Brenneman, J Hoinka, D Sant, M Cardone, G Trinchieri, TM Przytycka, A Berezhnoy |
Nucleic Acids Research | 2015 |
Screening and Identifying a Novel ssDNA Aptamer against Alpha-fetoprotein Using CE-SELEX
L Dong, Q Tan, W Ye, D Liu, H Chen, H Hu, D Wen, Y Liu, Y Cao, J Kang, J Fan, W Guo, W Wu |
Scientific Reports | 2015 |