ATDC Function in Human Pancreatic Adenocarcinoma

描述(申请人提供)：胰腺癌是一种致命的疾病，其特点是诊断晚，侵袭周围组织，早期转移，以及对治疗的抵抗。迫切需要开发高效的、基于机制的治疗方法来提高这些患者的存活率。我们最近发现，大多数人胰腺癌特异地过度表达D组共济失调(ATDC)相关基因。ATDC基因最初被描述为与遗传性疾病共济失调-毛细血管扩张(AT)有关，但后来被发现不是导致该疾病的基因，其功能仍不清楚。我们已经确定ATDC是一种新的DNA损伤反应基因，当暴露在化疗中时，它会给胰腺癌细胞带来生存优势。我们已经证明，DNA损伤后，ATDC运输到细胞核，对吉西他滨做出反应而被磷酸化，并定位于DNA修复焦点。ATDC的缺失导致对吉西他滨诱导的细胞凋亡的敏感性增加，并导致下游细胞周期检查点信号的缺陷。我们还发现，高水平的ATDC在体外和体内都对胰腺癌细胞具有生长优势。由于ATDC的过表达促进了β-连环蛋白的转录，因此ATDC对细胞增殖的刺激作用可能是由于增强了β-连环蛋白途径。我们证明ATDC与HIT家族蛋白HINT1相互作用，HINT1是β-连环蛋白途径的负调节因子，我们推测ATDC通过隔离HINT1刺激β-连环蛋白介导的增殖。在这项提案中，我们将探讨以下具体目标：1)研究ATDC在ATR介导的DNA损伤反应中的作用。2)评估ATDC的促癌能力是否与通过与HIT1家族蛋白HINT1相互作用而刺激β-连环蛋白途径有关。3)在临床前人胰腺癌原位移植模型中，分析靶向ATDC作为治疗手段的有效性。公共卫生相关性：我们认为ATDC是一种很有前途的胰腺癌新的治疗靶点，因为它的失活可能会导致肿瘤生长减少和对化疗的敏感性。

DESCRIPTION (provided by applicant): Pancreatic cancer is a deadly disease characterized by late diagnosis, aggressive invasion of surrounding tissues, early metastasis, and resistance to therapy. There is an urgent need to develop highly effective, mechanism-based therapies to improve survival in these patients. We have recently found that the majority of human pancreatic adenocarcinomas specifically over-express the gene for Ataxia-Telangiectasia Group D Associated (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 identified ATDC as a novel DNA damage response gene that confers a survival advantage to pancreatic cancer cells when exposed to chemotherapy. We have shown that following DNA damage, ATDC traffics to the nucleus, is phosphorylated in response to gemcitabine and localizes to DNA repair foci. Loss of ATDC results in increased sensitivity to gemcitabine-induced apoptosis and a defect in downstream cell cycle checkpoint signaling. We have also found that high levels of ATDC confer a growth advantage to pancreatic cancer cells both in vitro and in vivo. The ATDC-mediated stimulation of cell proliferation may be due to enhancement of the beta-catenin pathway since overexpression of ATDC increases beta-catenin mediated transcription. We demonstrate that ATDC interacts with the HIT family protein HINT1, a negative regulator of the beta-catenin pathway, and we hypthesize that ATDC stimulates beta-catenin-mediated proliferation by sequestering HINT1. In this proposal, we will explore the following specific aims: 1) To examine the role of ATDC in the ATR-mediated DNA damage response. 2) To assess if ATDC's tumor promoting ability is linked to stimulation of the beta-catenin pathway through interactions with the HIT1 family protein HINT1. 3) To analyze the efficacy of targeting ATDC as a therapeutic modality in a pre-clinical, primary human pancreatic cancer orthotopic xenograft model. PUBLIC HEALTH RELEVANCE: We propose that ATDC is a promising novel therapeutic target in pancreatic cancer because it's inactivation may lead to both reduced tumor growth and sensitization to chemotherapy.