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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114103-05
Application #
7560027
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (01))
Program Officer
Jessup, John M
Project Start
2005-04-01
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2009
Total Cost
$287,037
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Liau, Siong-Seng; Rocha, Flavio; Matros, Evan et al. (2008) High mobility group AT-hook 1 (HMGA1) is an independent prognostic factor and novel therapeutic target in pancreatic adenocarcinoma. Cancer 113:302-14
Liau, Siong-Seng; Whang, Edward (2008) HMGA1 is a molecular determinant of chemoresistance to gemcitabine in pancreatic adenocarcinoma. Clin Cancer Res 14:1470-7
Liau, S-S; Jazag, A; Ito, K et al. (2007) Overexpression of HMGA1 promotes anoikis resistance and constitutive Akt activation in pancreatic adenocarcinoma cells. Br J Cancer 96:993-1000
Duxbury, Mark S; Whang, Edward E (2007) RRM2 induces NF-kappaB-dependent MMP-9 activation and enhances cellular invasiveness. Biochem Biophys Res Commun 354:190-6
Liau, Siong-Seng; Ashley, Stanley W; Whang, Edward E (2006) Lentivirus-mediated RNA interference of HMGA1 promotes chemosensitivity to gemcitabine in pancreatic adenocarcinoma. J Gastrointest Surg 10:1254-62; discussion 1263
Liau, Siong-Seng; Jazag, Amarsanaa; Whang, Edward E (2006) HMGA1 is a determinant of cellular invasiveness and in vivo metastatic potential in pancreatic adenocarcinoma. Cancer Res 66:11613-22
Duxbury, Mark S; Ito, Hiromichi; Benoit, Eric et al. (2005) RNA interference demonstrates a novel role for integrin-linked kinase as a determinant of pancreatic adenocarcinoma cell gemcitabine chemoresistance. Clin Cancer Res 11:3433-8