Tissue Specific Radiation and Chemotherapy Sensitization of Prostate Cancer by

前列腺癌的组织特异性放射和化疗增敏

基本信息

批准号：
8379602
负责人：
SHAWN LUPOLD
金额：
$ 23.91万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8379602
关键词：
Antigen Targeting Apoptosis Ataxia Telangiectasia Biological Assay Cell Death Cell Line Cell Proliferation Cell Survival Cells Clinical Trials Core Biopsy Custom DNA Repair DNA Repair Pathway DNA repair protein DNA-dependent protein kinase Diagnosis Disease Disease-Free Survival Dose Gene Targeting Genomics Gleason Grade for Prostate Cancer Glutamate Carboxypeptidase II Goals Hour Human Hypersensitivity Immunohistochemistry In Vitro Inherited Injection of therapeutic agent Institutional Review Boards Ionizing radiation Laboratories Libraries Malignant neoplasm of prostate Measures Mediating Messenger RNA Modeling Morbidity - disease rate Mus Mutation Operative Surgical Procedures Organ PC3 cell line Pathway interactions Patients Pelvis Phase I Clinical Trials Principal Investigator Proliferation Marker Prostate Prostatic Prostatic Neoplasms Proteins RNA RNA Interference Radiation Radiation therapy Radical Prostatectomy Radio Radiosurgery Recruitment Activity Resected Reverse Transcriptase Polymerase Chain Reaction Safety Sampling Schedule Screening procedure Side Small Interfering RNA Specificity Staging System Testing Therapeutic Therapeutic Index Time Tissues Toxic effect Translating Translations Tumor Volume Weight Western Blotting advanced disease antigen binding aptamer base cancer cell chemotherapy high throughput screening improved in vivo in vivo Model intravenous injection knock-down manufacturing process mortality neoplastic cell novel novel strategies preclinical study programs protein expression research clinical testing success therapeutic target tumor tumor xenograft

项目摘要

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.

放射疗法是临床上局部前列腺癌（PCA）的两种主要治疗方法之一，是与高级，阶段和/或PSA相关的本地疾病的主要治疗。而辐射和手术的成功率对于低度器官限制疾病都是很高的，估计十个晚期疾病的无疾病生存小于50％。因此，一种改善的手段针对患有临床关注高阶段和/或年级前列腺癌患者的治疗指数显着降低了该疾病的发病率和死亡率。在此提案中，描述了一个模型来检验以下假设：局部治疗的治疗指数可以通过选择性敏化前列腺癌细胞对电离辐射来改善前列腺癌的癌症。在这里，基因组DNA损伤修复的自然途径将是治疗靶标。遗传这些途径中的突变，例如毛细血管理的共济失调，导致细胞超敏反应导致电离辐射（IR）。我们以前已经表明，哺乳动物癌细胞与通过通过RNA干扰（RNAI）疗法击倒DNA修复蛋白水平的IR。虽然很有希望该策略需要一种选择性靶向前列腺细胞的方法。我们现在提出三个具体目标开发一个通过靶向RNAi治疗选择性辐射敏化的模型。在AIM 1中，我们将确定在DNA修复途径中其他新型基因靶标的身份增强的辐射敏化。其次，在AIM 2中，我们将开发一个用于RNAi靶向的体内模型通过使用前列腺特异性膜抗原（PSMA）靶向RNA的辐射敏化适体在我们的实验室中发展。以前已应用这种适体XPSM-ALO来提供RNAi 对体内前列腺肿瘤细胞的治疗剂。最后，在AIM 3中，我们将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低。这些研究很棒开发第一个组织选择性辐射敏化剂并翻译新颖的潜力降低局部晚期前列腺癌的发病率和死亡率的策略。