P4 - ATDC as a Therapeutic Target in Pancreatic Cancer

胰腺癌是一种致命的疾病，其特点是诊断晚，侵袭性强， 组织、早期转移和对治疗的抗性。胰腺癌的分子基础是 不完全理解。我们最近发现大多数人胰腺癌 特异性过表达共济失调-毛细血管扩张症0组互补（ATDC）的基因。ATDC 该基因最初被描述为与遗传性疾病共济失调-毛细血管扩张症（AT）有关，但后来被 发现不是导致这种疾病的基因，它的功能仍然未知。我们发现 内源性ATDC的高水平表达赋予胰腺癌细胞生长优势 在体外和体内通过稳定β-连环蛋白。我们还发现ATDC是一种新的DNA 损伤反应基因，赋予暴露于辐射的胰腺癌细胞存活优势 治疗（RT）或化疗药物吉西他滨，它们是用于标准治疗的药剂。 胰腺癌患者。我们表明，ATDC交通的核心和损失的ATDC的结果， 辐射抗性DNA合成和下游细胞周期检查点激活信号传导中的缺陷。在这 建议，我们将研究ATDC功能的分子机制， 实验将检验ATDC是一种电离吉西他滨和RT的组合的假设。 在ATM和ATR介导的信号级联中重要的应激反应调节剂。而且我们 将分析靶向ATDC联合吉西他滨和RT作为治疗方式的效果 在胰腺癌中使用异种移植小鼠模型和包裹ATDC靶向的免疫脂质体 shRNA。这些临床前动物研究的结果将用作开发 临床试验，其中ATDC将在胰腺癌细胞中靶向，然后用 我们认为ATDC是一个有前途的新的治疗靶点，既可以减缓 胰腺肿瘤的生长，以及使它们更容易接受与以下组合的治疗： 吉西他滨和RT。

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.