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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：
7919414
负责人：
SHAWN LUPOLD
金额：
$ 24.63万
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/7919414
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 Neoplasms 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 Reproduction spores 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.

放射治疗是临床上局限性前列腺癌（PCa）的两种主要治疗方法之一