Colorectal cancer is the third most common cancer in the US, with approximately 145,000 new cases expected in 2005. Estimated 5-year survival rates range from 90% for patients with early diagnosis (stage I disease) and fall to <10% for patients with metastatic colorectal cancer (CRC). In this renewal application, we move to studies of the role of Reg IV in the development of mucosal cancers. Studies during the current funding period, presented as the foundation for this application, have demonstrated that: i) Expression of Reg IV is increased in adenomatous polyps and in CRCs, often to very high levels, ii) Increased expression Reg IV is one of the earliest steps in the formation of tumors, coinciding with the second spontaneous mutation in the APC gene and adenomatous change by histology in APCmin/+mice, iii) Reg IV is a potent activator of a signaling pathway (the EGFR-Akt-AP1) in CRC and leads to increased expression of Bcl-2, Bcl-XL, survivin and matrilysin. These genes have all previously been associated with a poor prognosis in advanced CRC, iv) Treatment of CRC cells with recombinant Reg IV protein significantly reduces their susceptibility to death by programed cell death (apoptosis), following radiation or chemotherapeutic drugs, and v) Function blocking anti-Reg IV mAbs or interfering RNAs have potent antagonistic effects on cell growth and increase susceptibility to apoptotic death following radiation or administration of chemotherapeutic drugs. By utilizing the approaches, outlined in the proposal, our goal is to better understand the mechanisms involved in the clinical resistance of CRC to conventional therapy and to ascertain the role of Reg IV as a cause of poor outcome. These studies will also provide new insight into the role of Reg IV antagonists and lay the groundwork for development of therapeutic reagents active in gastrointestinal adenocarcinomas.

Public Health Relevance

Colorectal cancer is the third most common cause of cancer and the second leading cause of cancer death. We identified a novel protein, Reg IV, which is an important regulator of tumor cell growth, invasion and resistance to treatment. These studies will provide critical insight into the potential role of Reg IV antagonists as a new treatment for gastrointestinal cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060106-08
Application #
8209296
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Hamilton, Frank A
Project Start
2001-07-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
8
Fiscal Year
2012
Total Cost
$312,246
Indirect Cost
$106,821
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Bluth, Martin H; Patel, Sameer A; Dieckgraefe, Brian K et al. (2006) Pancreatic regenerating protein (reg I) and reg I receptor mRNA are upregulated in rat pancreas after induction of acute pancreatitis. World J Gastroenterol 12:4511-6
Bishnupuri, Kumar S; Luo, Qizhi; Murmu, Nabendu et al. (2006) Reg IV activates the epidermal growth factor receptor/Akt/AP-1 signaling pathway in colon adenocarcinomas. Gastroenterology 130:137-49
Ahuja, Vineet; Dieckgraefe, Brian K; Anant, Shrikant (2006) Molecular biology of the small intestine. Curr Opin Gastroenterol 22:90-4
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Mukhopadhyay, Debnath; Jung, Jesse; Murmu, Nabendu et al. (2003) CUGBP2 plays a critical role in apoptosis of breast cancer cells in response to genotoxic injury. Ann N Y Acad Sci 1010:504-9
Li, A; Crimmins, D L; Luo, Q et al. (2003) Expression of a novel regenerating gene product, Reg IV, by high density fermentation in Pichia pastoris: production, purification, and characterization. Protein Expr Purif 31:197-206

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