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P4 - ATDC as a Therapeutic Target in Pancreatic Cancer

P4 - ATDC 作为胰腺癌的治疗靶点

基本信息

批准号：
7893337
负责人：
DIANE M SIMEONE
金额：
$ 18.23万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7893337
关键词：
ATM gene Adenocarcinoma Animals Apoptosis Ataxia Telangiectasia Cancer Model Cancer Patient Cancer cell line Cell Cycle Checkpoint Cell Nucleus Clinical Clinical Trials Complement DNA Damage DNA biosynthesis Defect Development Diagnosis Disease Gene Expression Genes Growth Hereditary Disease Human Immunoliposome In Vitro Ionizing radiation Lead Life Malignant neoplasm of pancreas Mediating Modality Molecular Neoplasm Metastasis Outcome Pancreatic Adenocarcinoma Pathway interactions Pharmaceutical Preparations Phase I Clinical Trials Role Serine Signal Transduction Testing The Sun Therapeutic Tissues Toxic effect Xenograft procedure base beta catenin biological adaptation to stress cancer cell gemcitabine improved in vivo mouse model nanovector new therapeutic target novel overexpression pancreatic neoplasm pre-clinical research study response small hairpin RNA standard care therapeutic target therapy resistant trafficking tumor tumor growth

项目摘要

Pancreatic cancer is a deadly disease characterized by late diagnosis, aggressive invasion of sun'ounding tissues, eariy metastasis, and resistance to therapy. The molecular basis of pancreatic cancer is incompletely understood. We have recently found that the majority of human pancreatic adenocarcinomas specifically over-express the gene for Ataxia-Telangiectasia Group 0 Complemented (ATDC). The ATDC gene was initially described in association with the genetic disorder ataxia-telangiectasia (AT) but was later found not to be the gene responsible for that disorder, and it's function remained unknown. We have found that high levels of expression of endogenous ATDC confer a growth advantage of pancreatic cancer cells both in vitro and in vivo by stabilization of beta-catenin. We have also identified ATDC as a novel DNA damage response gene that confers a survival advantage to pancreatic cancer cells exposed to iradiation therapy (RT) or the chemotherapeutic drug gemcitabine which are agents used for standard care of pancreatic cancer patients. We show that ATDC traffics to the nucleus and that loss of ATDC results in radioresistant DNA synthesis and a defect in downstream cell cycle checkpoint activation signaling. In this proposal, we will investigate the molecular mechanisms by which ATDC functions in the response to the combination of ionzing gemcitabine and RT. The experiments will test the hypothesis that ATDC is an important stress response regulator in both ATM- and ATR-mediated signaling cascades. Furthermore, we will analyze the effect of targeting ATDC in combination with gemcitabine and RT as a therapeutic modality in pancreatic cancer using a xenograft mouse model and immunoliposomes canning ATDC-targeting shRNA. The results from these preclinical animal studies will be used as a guide in the development of a clinical trial where ATDC will be targeted in pancreatic cancer cells prior to standard treatment with gemcitabine and RT. We propose that ATDC is a promising novel therapeutic target for both slowing the growth of pancreatic tumors as well as making them more susceptible to treatment with the combination of gemcitabine and RT.

胰腺癌是一种以晚期诊断、恶性侵袭为特征的致命疾病