Tissue-Specific Radiation Sensitization of Prostate Cancer by Aptamer-Targeted siRNA Knock-Down of DNA Repair Pattiway

本项目的长期目标是提高前列腺癌放射治疗的治疗指数。放射治疗是临床局限性前列腺癌的两种主要治疗方法之一，也是与较高级别、分期和/或PSA相关的局部晚期疾病的主要治疗方法。虽然低级别器官受限疾病的放疗和手术成功率都很高，但晚期疾病的估计十年无病生存率不到50%。因此，改善临床上高分期和/或分级前列腺癌患者的治疗方法将显著降低该病的发病率和死亡率。为了解决这个问题，我们开发了前列腺靶向RNA干扰(RNAi)试剂，选择性地抑制前列腺细胞中的DNA修复途径。组织特异性靶向是通过RNA适配子A10-3实现的，它与细胞表面的前列腺特异性膜抗原(PSMA)结合，然后内化到细胞内。然后，结合的短发夹状RNA(ShRNAs)被细胞RNAi机制处理，导致特定的DNA修复mRNA和蛋白质被击倒。在之前的资金周期中，我们证明了当这些药物直接注射到肿瘤中时，显著提高了外照射治疗的治疗指数。在这里，我们建议通过产生化学合成的适体siRNA辐射增敏剂并在I期临床试验中评估它们作为前列腺腔内注射剂的安全性来继续这一策略的发展。除了这一翻译目标外，我们还将进行临床前研究，以确定适体-siRNA辐射增敏剂在静脉注射后是否有效。如果成功，这种给药模式将为局部先进的PCA提供放射增敏的第二途径，它将为提高外照射治疗骨痛的疗效提供一种新的手段，最后它将提供一种提高系统靶向放射治疗效果的手段。

The long term objective of this project is to improve the therapeutic index of radiation therapy for the treatment of prostate cancer (PCa). Radiation therapy is one of two primary treatments for clinically-localized PCa and is the principal therapy for locally-advanced disease associated with a higher grade, stage and/or PSA. While the success rate for both radiation and surgery is high for low-grade organ-confined disease, the estimated ten year disease-free-survival for advanced disease is less than 50%. Therefore, a means to improve the treatment of patients with clinically-localized high stage and/or grade prostate cancer would significantly decrease the morbidity and mortality of this disease. To address this we developed prostate-targeted RNA interference (RNAi) agents that selectively inhibit DNA repair pathways in prostate cells. Tissue-specific targeting was achieved through an RNA aptamer, A10-3, which binds to the Prostate Specific Membrane Antigen (PSMA) on the cellular surface and is then internalized into cells. The conjugated short hairpin RNAs (shRNAs) are then processed by cellular RNAi machinery, leading to knockdown of specific DNA repair mRNA and proteins. In the previous funding cycle we demonstrated that these agents, when directly injected into the tumor, significantly enhance the therapeutic index of external beam radiation therapy. Here we propose to continue the development of this strategy by generating chemically synthesized aptamer-siRNA radiation sensitizing agents and evaluating their safety as intraprostatically injected agents in a Phase I clinical trial. In addition to this translational aim, we will perform pre-clinical studies to determine whether the aptamer-siRNA radiation sensitizing agents are effective following intravenous injection. If successful, this mode of administration would provide a secondary route for radio-sensitizing locally advanced PCa, it would provide a novel means to improve the efficacy of external beam radiation therapy for the management of bone pain, and finally it would provide a means to enhance the efficacy of systemically targeted radiotherapeutics.