Tissue Specific Radiation and Chemotherapy Sensitization of Prostate Cancer by

放射治疗是临床局限性前列腺癌（PCa）的两种主要治疗方法之一， 与较高级别、分期和/或PSA相关的局部晚期疾病的主要治疗。而 放射和手术的成功率对于低度器官局限性疾病是很高的， 晚期疾病的无病生存率低于50%。因此，一种改善 临床局部高分期和/或高分级前列腺癌患者的治疗指数 大大降低了该病的发病率和死亡率。 在这个建议中，描述了一个模型来检验局部治疗的治疗指数 可以通过选择性地使前列腺癌细胞对电离辐射敏感来改善前列腺癌的预后。 在这里，基因组DNA损伤修复的天然途径将成为治疗靶点。继承 这些途径中的突变，例如共济失调毛细血管扩张症，导致细胞对电离 辐射（IR）。我们先前已经证明，哺乳动物癌细胞对 通过RNA干扰（RNAi）治疗敲低DNA修复蛋白水平的IR。虽然前景看好， 该策略需要选择性靶向前列腺细胞的手段。我们现在提出三个具体目标， 通过靶向RNAi疗法开发前列腺癌细胞的选择性辐射敏化模型。 在目标1中，我们将确定DNA修复途径中其他新基因靶点的身份， 增强辐射敏感性。其次，在目标2中，我们将开发一种用于RNAi靶向的体内模型 和通过使用前列腺特异性膜抗原（PSMA）靶向RNA的辐射敏化 我们实验室开发的适体。这种适体，xPSM-AlO，先前已被应用于递送RNAi， 前列腺肿瘤细胞的治疗剂。最后，在目标3中，我们将这些临床前研究扩展到 I期临床试验，以确定安全性和选择性靶基因敲除。这些研究有很大的 开发第一种组织选择性辐射增敏剂和翻译一种新的 降低局部晚期前列腺癌发病率和死亡率的策略。

Radiation therapy is one of two primary treatments for clinically-localized prostate cancer (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 therapeutic index for patients with clinically-localized high stage and/or grade prostate cancer would significantly decrease the morbidity and mortality of this disease. In this proposal, a model is described to test the hypothesis that the therapeutic index for local treatment of prostate cancer can be improved by selectively sensitizing prostatic cancer cells to ionizing radiation. Here, the natural pathways of genomic DNA damage repair will be the therapeutic target. Inherited mutations in these pathways, such as in Ataxia Telangiectasia, result in cellular hypersensitivity to ionizing radiation (IR). We have previously shown that mammalian cancer cells be made similarly hypersensitive to IR by knocking down DNA repair protein levels through RNA interference (RNAi) therapy. While promising, this strategy requires a means to selectively target prostatic cells. We now propose three specific aims to develop a model for selective radiation sensitization of prostate cancer cells through targeted RNAi therapy. In Aim 1, we will determine the identity of additional novel gene targets in DNA repair pathways for enhanced radiation sensitization. Secondly, in Aim 2, we will develop an in vivo model for RNAi targeting and radiation sensitization through the use of a Prostate Specific Membrane Antigen (PSMA) targeting RNA aptamer developed in our laboratory. This aptamer, xPSM-AlO, has been previously applied to deliver RNAi therapeutics to prostate tumor cells in vivo. Lastly, in Aim 3, we will extend these pre-clinical studies to a phase I clinical trial to determine safety and selective target gene knock-down. These studies have great potential in developing the first tissue-selective radiation sensitization agent and in translating a novel strategy to decrease the morbidity and mortality of locally advanced prostate cancer.