Biomarkers and Therapeutic Targets in Pancreatic Cancer

胰腺癌的生物标志物和治疗靶点

• 批准号: 6912067
• 负责人: EDWARD E WHANG
• 金额: $ 30.27万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6912067
• 关键词: adenocarcinoma; antineoplastics; athymic mouse; biological signal transduction; biomarker; cancer registry /resource; cell adhesion molecules; clinical research; drug resistance; enzyme structure; gemcitabine; gene expression; glycosylphosphatidylinositols; human data; human tissue; neoplasm /cancer invasiveness; neoplastic process; nuclear factor kappa beta; pancreas neoplasms; prognosis; protein kinase; ribonucleotide reductase

DESCRIPTION (provided by applicant): Carcinoembyronic antigen-related cell adhesion molecule 6 (CEACAM6) is a glycosylphosphatidylinositol (GPI)-linked protein that we have shown is overexpressed in pancreatic adenocarcinoma and in advanced pancreatic intraepithelial neoplasia (PanIN) lesions. Patients with CEACAM6-positive pancreatic adenocarcinomas have poorer postoperative survival than patients with CEACAM6-negative cancers. Our studies suggest that CEACAM6 promotes: 1) invasiveness, and 2) chemoresistance to gemcitabine (the principal chemotherapeutic agent used for treating patients with advanced pancreatic cancer). These studies also suggest that ribonucleotide reductase M2 subunit (RRM2), itself a downstream target of CEACAM6 signaling, plays a critical role in mediating resistance to gemcitabine. We have shown that targeted therapy directed against either CEACAM6 or RRM2 inhibits tumor progression and attenuates resistance to gemcitabine-induced cytotoxicity in experimental pancreatic cancer. We now propose to characterize downstream effectors of CEACAM6 and RRM2 signaling. Based on our preliminary data, we have formulated three specific aims: 1. To test the hypothesis that CEACAM6 over expression promotes cellular invasive potential through a c-Src- and Akt-dependent mechanism in pancreatic cancer. 2. To test the hypothesis that RRM2 over expression promotes resistance to gemcitabine-induced cytotoxicity through a Raf-1-, protein kinase CK2-, and NF-kB-dependent mechanism in pancreatic cancer. 3. To test the hypothesis that CEACAM6 and RRM2 signaling pathway components are coordinately expressed in pancreatic adenocarcinomas and in PanIN lesions. By characterizing CEACAM6 and RRM2 signaling pathways, we hope to identify: 1) novel therapeutic targets, 2) new prognostic factors, and 3) early detection strategies for pancreatic cancer.

描述（由申请人提供）：癌胚抗原相关细胞粘附分子 6 (CEACAM6) 是一种糖基磷脂酰肌醇 (GPI) 连接蛋白，我们已证明其在胰腺腺癌和晚期胰腺上皮内瘤变 (PanIN) 病变中过度表达。 CEACAM6 阳性胰腺癌患者的术后生存率低于 CEACAM6 阴性癌症患者。我们的研究表明，CEACAM6 促进：1) 侵袭性，2) 对吉西他滨（用于治疗晚期胰腺癌患者的主要化疗药物）的化疗耐药性。这些研究还表明，核糖核苷酸还原酶 M2 亚基 (RRM2) 本身是 CEACAM6 信号传导的下游靶标，在介导吉西他滨耐药性中发挥着关键作用。我们已经证明，针对 CEACAM6 或 RRM2 的靶向治疗可抑制实验性胰腺癌中的肿瘤进展并减弱对吉西他滨诱导的细胞毒性的耐药性。我们现在建议表征 CEACAM6 和 RRM2 信号传导的下游效应器。根据我们的初步数据，我们制定了三个具体目标： 1. 检验胰腺癌中 CEACAM6 过度表达通过 c-Src 和 Akt 依赖性机制促进细胞侵袭潜力的假设。 2. 检验以下假设：在胰腺癌中，RRM2 过度表达通过 Raf-1、蛋白激酶 CK2 和 NF-kB 依赖性机制促进对吉西他滨诱导的细胞毒性的抵抗。 3. 检验CEACAM6和RRM2信号通路成分在胰腺腺癌和PanIN病变中协调表达的假设。 通过表征 CEACAM6 和 RRM2 信号通路，我们希望确定：1）新的治疗靶点，2）新的预后因素，以及 3）胰腺癌的早期检测策略。