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：
8116705
负责人：
SHAWN LUPOLD
金额：
$ 24.6万
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
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8116705
关键词：
Antigen Targeting Apoptosis Ataxia Telangiectasia Biological Assay Cancerous 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 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 Research Ethics Committees 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.

放射治疗是临床局限性前列腺癌 (PCa) 的两种主要治疗方法之一，也是与较高级别、阶段和/或 PSA 相关的局部晚期疾病的主要治疗方法。虽然对于低度器官局限性疾病，放疗和手术的成功率都很高，估计有 10 晚期疾病的年无病生存率低于 50%。因此，有一种方法可以改善临床局部高阶段和/或分级前列腺癌患者的治疗指数将显着降低该病的发病率和死亡率。在该提案中，描述了一个模型来检验局部治疗的治疗指数的假设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发生。在这里，基因组 DNA 损伤修复的自然途径将成为治疗目标。遗传这些途径的突变，例如毛细血管扩张性共济失调，会导致细胞对电离超敏反应辐射（IR）。我们之前已经证明，哺乳动物癌细胞对以下物质同样高度敏感：通过 RNA 干扰 (RNAi) 疗法降低 DNA 修复蛋白水平来进行 IR。在充满希望的同时，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通过靶向 RNAi 治疗开发前列腺癌细胞选择性放射增敏模型。在目标 1 中，我们将确定 DNA 修复途径中其他新基因靶标的身份增强辐射敏感性。其次，在目标2中，我们将开发RNAi靶向的体内模型通过使用靶向 RNA 的前列腺特异性膜抗原 (PSMA) 实现放射增敏适体是我们实验室开发的。该适配体 xPSM-AlO 先前已用于递送 RNAi 体内前列腺肿瘤细胞的治疗。最后，在目标 3 中，我们将把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。这些研究有很大开发第一种组织选择性辐射增敏剂和转化新型药物的潜力降低局部晚期前列腺癌发病率和死亡率的策略。