The colon cancer (CRC) staging, at the time of disease diagnosis, is critical for patient survival, which ranges from 90% for patients with localized disease to meagre 13% for the ones with metastasis. Thus, improved understanding of the molecular regulation of CRC-progression and metastasis is critical and urgent, to develop novel therapies. In this regard, studies from our, and other laboratories, have provided strong support for a casual role for upregulated claudin- 1 expression in promoting CRC malignancy, especially metastasis. An upregulated (and mislocalized) claudin-1 expression in CRC patient samples associated predominantly with CRC metastasis to liver (58%) and lymph nodes (35%). Moreover, genetic manipulation of claudin-1 expression was sufficient to modulate metastatic ability of CRC cells lines in vitro and in vivo. Further analysis suggested essential roles of proto-oncogenes Src and EphA2 in claudin-1 mediated CRC progression. The key objectives of this proposal are to determine the roles of Src- and EphA2-signaling in fostering CRC malignancy under conditions of the dysregulated claudin- 1 expression, and preclinical testing of a novel claudin-1 inhibitor for its therapeutic efficacy in inhibiting CRC malignancy. To test our hypothesis we propose following studies:
Specific Aim - 1. To determine how dysregulated claudin-1 expression promotes dissemination of colon cancer cell and metastasis;
and Specific Aim -2. To test therapeutic efficacy of a novel anti-claudin-1 small molecule inhibitor (I-6) in inhibiting CRC malignancy. The outcome of this study are expected to have substantial impact on prevention/inhibition of CRC metastasis.

Public Health Relevance

Colorectal cancer endangers males and females of all the population however the US (the United States of America) Veterans show a higher incidence rate of colon cancer than the general population. It is estimated that each year the Veterans affairs manages and treats ~175,000 CRC patients. It is therefore an urgent necessity to find novel therapeutic strategies to curb CRC- malignancy to increase the survival for U.S. Veterans with CRC. Claudin-1, a tight junction protein, is highly upregulated in CRC and its expression correlates with CRC metastasis in colon cancer cells, mouse models and human patient population. Our aim is to understand how dysregulated claudin-1 expression affects metastatic ability of CRC cells, in order to define ways to harness its use as a target molecule to inhibit CRC-progression. Additionally, we plan to perform pre-clinical testing of a novel inhibitor effective in curbing claudin-1 dependent promotion of CRC malignancy.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX002086-06A1
Application #
9558159
Study Section
Oncology C (ONCC)
Project Start
2013-07-01
Project End
2022-09-30
Budget Start
2018-10-01
Budget End
2019-09-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Omaha VA Medical Center
Department
Type
DUNS #
844360367
City
Omaha
State
NE
Country
United States
Zip Code
68105
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Bhat, A A; Pope, J L; Smith, J J et al. (2015) Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis. Oncogene 34:4570-80
Ahmad, R; Chaturvedi, R; Olivares-Villagómez, D et al. (2014) Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis. Mucosal Immunol 7:1340-53