Biomarkers and Therapeutic Targets in Pancreatic Cancer

描述(申请人提供)：癌胚抗原相关细胞黏附分子6(CEACAM6)是一种糖基磷脂酰肌醇(GPI)连接的蛋白，我们已经证明在胰腺癌和晚期胰腺上皮内瘤变(Panin)病变中过表达。CEACAM6阳性的胰腺癌患者术后生存率比CEACAM6阴性的患者差。我们的研究表明，CEACAM6促进了：1)侵袭性，以及2)对吉西他滨(治疗晚期胰腺癌的主要化疗药物)的耐药性。这些研究还表明，核糖核苷酸还原酶M2亚基(RRM2)本身就是CEACAM6信号的下游靶点，在介导吉西他滨耐药中发挥着关键作用。我们已经证明，针对CEACAM6或RRM2的靶向治疗可以抑制实验性胰腺癌的肿瘤进展，并减轻对吉西他滨诱导的细胞毒性的耐药性。我们现在建议对CEACAM6和RRM2信号的下游效应器进行表征。根据我们的初步数据，我们制定了三个具体的目标：1.验证CEACAM6过表达通过c-Src和Akt依赖的机制促进胰腺癌细胞侵袭潜能的假设。2.验证RRM2过表达通过Raf-1、蛋白激酶CK2和NF-kB依赖的机制促进胰腺癌对吉西他滨诱导的细胞毒的抵抗的假说。3.验证CEACAM6和RRM2信号通路成分在胰腺癌和胰腺癌皮损中协同表达的假说。通过对CEACAM6和RRM2信号通路的研究，我们希望确定：1)新的治疗靶点，2)新的预后因素，3)胰腺癌的早期检测策略。

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.