Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts
Xiaohua Ni, … , Theodore L. DeWeese, Shawn E. Lupold
Xiaohua Ni, … , Theodore L. DeWeese, Shawn E. Lupold
Published May 9, 2011
Citation Information: J Clin Invest. 2011;121(6):2383-2390. https://doi.org/10.1172/JCI45109.
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Research Article Oncology

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

Xiaohua Ni, Yonggang Zhang, Judit Ribas, Wasim H. Chowdhury, Mark Castanares, Zhewei Zhang, Marikki Laiho, Theodore L. DeWeese, Shawn E. Lupold

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Figure 5

Radiosensitization in PCa cell and tumor models.

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Radiosensitization in PCa cell and tumor models. (A) In vitro radiosensi...
(A) In vitro radiosensitization. LNCaP cells treated with 400 nM A10-3–DNAPK or A10-3–Con or transfected with control siRNA were irradiated 48 hours later with 6 Gy IR, and cell viability was assessed 12 days later by MTS. Percent cell death is relative to nonirradiated cells. (B–D) In vivo radiosensitization. Established tumors were treated with aptamer-shRNA chimeras (days –3 and –2) and either 6 Gy IR or no radiation (day 0). (B) PC3 tumor model (n = 3 per group). A10-3–DNAPK provided no significant therapeutic benefit to nonirradiated or irradiated PC3 tumors. Radiation similarly affected growth in all treatment groups. Mean ± SEM. (C) LNCaP tumor model (n ≥ 6 per group). Radiation similarly affected growth in all treatment groups except irradiated A10-3–DNAPK. *P < 0.05, ***P < 0.001, A10-3–DNAPK IR vs. A10-3–Con IR and A10-3–DNAPK IR vs. Neg-DNAPK IR; 2-way ANOVA. Mean ± SEM. (D) Extension of tumor quadrupling for LNCaP tumor model. Events (animals whose tumor volume was not yet 4-fold the size at injection) were plotted by Kaplan-Meier curve. P < 0.01, A10-3–Con IR vs. A10-3–Con and Neg-DNAPK IR vs. Neg-DNAPK; P < 0.0001, A10-3–DNAPK IR vs. A10-3–Con IR and A10-3–DNAPK IR vs. Neg-DNAPK IR; log-rank (Mantel-Cox) test.