Abstract
Abstract Dose-escalated radiation therapy for localized prostate cancer (PCa) has a clear therapeutic benefit; however, escalated doses may also increase injury to non-cancerous tissues. Radiation-sensitizing agents can improve ionizing radiation (IR) potency, but without targeted delivery these agents will also sensitize surrounding normal tissues. Here we describe the development and application of prostate-targeted RNA interference agents which selectively sensitize PSMA-positive cells to IR. A high throughput siRNA screen identified DNA-PK, MAD2L2, BRCA2, NBN, RAD23B, and RAD54L as candidate DNA-repair pathway targets for prostate cancer radio-sensitization. When candidate shRNAs were conjugated to the PSMA-targeting RNA aptamer, A10-3, they were selectively delivered into PSMA positive prostate cancer cells in the absence of traditional transfection reagents. The shRNA portion was then processed by dicer to the corresponding siRNA. DNA-PK shRNAs, delivered by PSMA-targeting RNA aptamers, selectively reduced DNA-PK in PCa cells, xenografts and human prostate tissues. The mechanism of DNA-PK knock-down was confirmed to be through RNA interference by 5’-RACE assay. In tumor injection models A10-3-DNA-PK-shRNAs, combined with IR, dramatically and specifically enhanced PSMA-positive tumor response to IR. This treatment extended time to reach quadruple tumor volume by approximately 10 weeks when compared to only one week in tumors treated with radiation and control aptamer-shRNAs. A10-3-DNA-PK-shRNA and radiation had no affect on the PSMA negative PC-3 tumors. These studies support aptamer-shRNAs as selective sensitizing agents which may improve the treatment of high-risk localized PCa. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5387. doi:10.1158/1538-7445.AM2011-5387
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
