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Biomarkers and Therapeutic Targets in Pancreatic Cancer

胰腺癌的生物标志物和治疗靶点

基本信息

批准号：
7560027
负责人：
EDWARD E WHANG
金额：
$ 28.7万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2011-02-28
项目状态：
已结题

项目摘要

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（由申请方提供）：癌胚抗原相关细胞粘附分子6（CEACAM 6）是一种糖基磷脂酰肌醇（GPI）连接蛋白，我们已证明其在胰腺癌和晚期胰腺上皮内瘤变（PanIN）病变中过表达。CEACAM 6阳性胰腺癌患者的术后生存率低于CEACAM 6阴性患者。我们的研究表明，CEACAM 6促进：1）侵袭性，和2）对吉西他滨（用于治疗晚期胰腺癌患者的主要化疗药物）的耐药性。这些研究还表明，核糖核苷酸还原酶M2亚基（RRM 2）本身是CEACAM 6信号传导的下游靶点，在介导吉西他滨耐药性中起着关键作用。我们已经表明，针对CEACAM 6或RRM 2的靶向治疗抑制肿瘤进展并减弱对实验性胰腺癌中吉西他滨诱导的细胞毒性的抗性。我们现在提出表征CEACAM 6和RRM 2信号传导的下游效应物。根据我们的初步数据，我们制定了三个具体目标：1。检验CEACAM 6过表达通过c-Src和Akt依赖性机制促进胰腺癌细胞侵袭潜力的假设。2.检验RRM 2过表达通过Raf-1、蛋白激酶CK 2和NF-κ B依赖性机制促进胰腺癌对吉西他滨诱导的细胞毒性耐药的假设。3.检验CEACAM 6和RRM 2信号通路组分在胰腺癌和PanIN病变中协调表达的假设。通过表征CEACAM 6和RRM 2信号通路，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。