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KiSS1 treatment of pancreatic adenocarcinoma

KiSS1 治疗胰腺癌

基本信息

批准号：
8518260
负责人：
Lacey R McNally
金额：
$ 22.7万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-21 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8518260
关键词：
Address Adenoviruses Animal Model Animals Apoptosis Biological Models Bioluminescence Blood Breast Melanoma Cancer Etiology Cancer Patient Cells Cessation of life Cherry - dietary Chronic Disease Clinical Clinical Trials Combination Drug Therapy Cytostatics Cytotoxic Chemotherapy Data Diagnosis Disease Early treatment Enzyme-Linked Immunosorbent Assay Evaluation Failure Future Goals Grant Growth Hematoxylin and Eosin Staining Method Hepatic Histology Hour Human Image Immunohistochemistry Implant In Situ Nick-End Labeling In Vitro Infection Injection of therapeutic agent Instruction Investigation Label Liver Luciferases Lung Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Measures Messenger RNA Metastatic Lesion Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Metastatic Pancreatic Adenocarcinoma Methods Modeling Monitor Morphology Mus Neoplasm Metastasis Organ Pancreas Pancreatic Adenocarcinoma Patients Pharmaceutical Preparations Plasmids Preparation Primary Neoplasm Principal Investigator Progress Reports Protein Analysis Proteins Proto-Oncogene Proteins c-akt Publishing Research Respiratory Diaphragm Route SCID Mice Sampling Signal Transduction Staging Subgroup Survival Rate System Testing Therapeutic Therapeutic Agents Time Tissues Transfection Treatment Efficacy United States Update Viral Virus Western Blotting Xenograft Model Xenograft procedure base bioluminescence imaging cancer cell chemotherapeutic agent chemotherapy conditionally replicative adenovirus cytotoxic design fluorescence imaging gene therapy implantation improved in vivo in vivo Model mouse model neoplastic cell novel therapeutic intervention p65 pancreas xenograft pancreatic cancer cells pancreatic neoplasm prevent programs research study response restoration tumor tumor growth tumor xenograft

项目摘要

Currently, pancreatic adenocarcinonna is the 4th leading cause of cancer death in the United States with a median survival of <6 month and a dismal 5-yr survival rate of 1-3%. The majority of patients diagnosed with pancreatic adenocarcinoma have disseminated disease at the time of diagnosis. Because clinical trials performed over the last 30 years also clearly demonstrated that only minimal progress has been made in patient survival, new strategies are desperately needed. The goal of this research is to develop a novel therapeutic approach using a metastasis suppressor to treat metastatic pancreatic adenocarcinoma and thereby improve patient survival. The metastasis suppressor, KiSS1, is a secreted protein that inhibits metastasis of human melanoma, breast, and ovarian cancer xenograft models. KiSSI expression levels are significantly lower in pancreatic cancer tissues from patients than normal pancreatic tissues. The hypothesis of this proposal is that metastasis of pancreatic adenocarcinoma can be significantly reduced (or prevented) by therapeutic strategies including KiSSI, a metastasis suppressor. Preliminary studies indicate that restoration of KiSSI greatly reduces both hepatic (97.5%) and pulmonary metastasis (99.4%) of pancreatic cancer in an orthotopic xenograft mouse model. Building upon these data, the proposed in vitro and in vivo experiments will evaluate the efficacy of KiSSI treatment alone, or combined with chemotherapy. Importantly, since KiSSI is a secreted, cytostatic protein, this strategy does not depend on restoration of KiSSI in all cancer cells. Rather, the effects of KiSSI are local, including via a by-stander effect, and systemic, due to secretion of KiSSI. Specific aim #1 will evaluate treatment of metastatic pancreatic cells transfected with KiSSI plasmid with chemotherapy in a xenograft mouse model. Aim #2 will address KiSSI delivery, and enable testing of KiSSI in a model system by producing a KiSSI-expressing adenovirus. Aim #3 will evaluate the treatment of metastatic tumors with the Ad-KiSS1 virusi Specific aim #4 will evaluate combination treatment with Ad-KiSS1 virus and chemotherapy in established metastatic and primary tumors in a xenograft model.

目前，胰腺癌是美国癌症死亡的第四大原因，中位生存期<6个月，5年生存率低，为1- 3%。大多数被诊断为胰腺癌在诊断时已经扩散。由于临床试验在过去30年中进行的研究也清楚地表明，在这方面只取得了最小的进展，患者生存，迫切需要新的策略。这项研究的目的是开发一种新的使用转移抑制剂治疗转移性胰腺癌的治疗方法，从而提高患者存活率。转移抑制因子KiSS 1是一种分泌性蛋白，人黑素瘤、乳腺癌和卵巢癌异种移植模型的转移。KiSSI表达水平为在来自患者的胰腺癌组织中显著低于正常胰腺组织。的假设这一建议的一个优点是可以显著减少（或预防）胰腺癌的转移，通过治疗策略，包括KiSSI，一种转移抑制剂。初步研究表明， KiSSI的恢复大大减少了胰腺癌的肝转移（97.5%）和肺转移（99.4%）。原位异种移植小鼠模型中的癌症。基于这些数据，提出了体外和体内实验将评估KiSSI单独治疗或与化疗联合治疗的功效。重要的是，由于KiSSI是一种分泌的细胞抑制蛋白，因此这种策略不依赖于KiSSI的恢复。 KiSSI在所有癌细胞中。相反，KiSSI的影响是局部的，包括通过旁观者效应，由于KiSSI的分泌，全身性。具体目标#1将评价转移性胰腺细胞的治疗在异种移植小鼠模型中，用KiSSI质粒转染并进行化疗。目标#2将解决KiSSI问题递送，并且能够通过产生表达KiSSI的腺病毒在模型系统中测试KiSSI。目的 #3将评估使用Ad-KiSS 1病毒治疗转移性肿瘤的效果，具体目标#4将评估 Ad-KiSS 1病毒和化疗联合治疗已确定的转移性和原发性肿瘤在异种移植模型中。