Colon cancers are the second leading cause of cancer-related deaths in the United States. Although the genetic alternations associated with initiation and progression of colon cancers are well defined, the mechanisms by which tumors invade and metastasize require further investigation. Metastasis of colon cancers is the major cause of patient deaths. Thus, understanding the mechanisms of tumor metastasis is important and likely to be clinically useful. RON (Recepteur d'Origine Nantais) is a receptor tyrosine kinase belonging to the MET proto-oncogene family. Recent studies have shown that RON and its variants are highly expressed and constitutively activated in the majority of colon carcinoma cells, but not in normal colon mucosa or benign lesions. Moreover, RON activation induces a unique genetic program leading to cell dissociation, migration and matrix invasion. These data suggest that RON might be involved in the invasive growth and metastasis of colon cancers in vivo. The goal of this project is to study the cellular and molecular mechanisms by which RON mediates the invasive growth of colon carcinoma cells. The hypotheses underlying this proposal are: a) Cellular disorganization and genetic changes during the progression of colon cancers results in increased RON expression and its variant formation; b) RON has oncogenic/metastatic potential which is essential for the acquisition of motile-invasive phenotypes in colon cancers; and c) Acquisition of motile-invasive phenotypes by colon cancer cells is determined by the intracellular domains of RON that transduce a unique signaling pathway(s). To test these hypotheses, our studies will focus on: 1. Correlating RON and its variant expression in colon carcinoma cells with invasive behavior and clinical outcomes; 2. Determining the potential cellular mechanisms responsible for the abnormal RON expression and activation; 3. Studying how RON activation causes oncogenic and invasive activity in colon cancers cells; 4. Investigating the unique signaling pathway(s) of RON and its variants that elicit motile-invasive phenotypes in colon cancer cells. This work is important for several reasons. First, it will provide the basis for understanding the role of RON in the progression of colon cancers, particularly at the metastatic stages. Second, it will facilitate our understanding the mechanisms of how overexpression of a particular receptor tyrosine kinase results in the invasive growth and metastasis of colon cancers. Further, this work may lead to novel approaches for decreasing the metastasis of colon cancers in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA091980-04
Application #
6755009
Study Section
Pathology B Study Section (PTHB)
Program Officer
Ault, Grace S
Project Start
2002-06-05
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$264,330
Indirect Cost
Name
Texas Tech University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
Feng, Liang; Yao, Hang-Ping; Zhou, Yong-Qing et al. (2016) Biological evaluation of antibody-maytansinoid conjugates as a strategy of RON targeted drug delivery for treatment of non-small cell lung cancer. J Exp Clin Cancer Res 35:70
Yao, Hang-Ping; Feng, Liang; Zhou, Jian-Wei et al. (2016) Therapeutic evaluation of monoclonal antibody-maytansinoid conjugate as a model of RON-targeted drug delivery for pancreatic cancer treatment. Am J Cancer Res 6:937-56
Nag, Subhasree; Qin, Jiang-Jiang; Voruganti, Sukesh et al. (2015) Development and validation of a rapid HPLC method for quantitation of SP-141, a novel pyrido[b]indole anticancer agent, and an initial pharmacokinetic study in mice. Biomed Chromatogr 29:654-63
Feng, Liang; Wang, Wei; Yao, Hang-Ping et al. (2015) Human tumor xenografts in mouse as a model for evaluating therapeutic efficacy of monoclonal antibodies or antibody-drug conjugate targeting receptor tyrosine kinases. Methods Mol Biol 1233:151-9
Sharma, Sharad; Yao, Hang-Ping; Zhou, Yong-Qing et al. (2014) Prevention of BMS-777607-induced polyploidy/senescence by mTOR inhibitor AZD8055 sensitizes breast cancer cells to cytotoxic chemotherapeutics. Mol Oncol 8:469-82
Zeng, Jun-Ying; Sharma, Sharad; Zhou, Yong-Qing et al. (2014) Synergistic activities of MET/RON inhibitor BMS-777607 and mTOR inhibitor AZD8055 to polyploid cells derived from pancreatic cancer and cancer stem cells. Mol Cancer Ther 13:37-48
Wang, Wei; Qin, Jiang-Jiang; Voruganti, Sukesh et al. (2014) Identification of a new class of MDM2 inhibitor that inhibits growth of orthotopic pancreatic tumors in mice. Gastroenterology 147:893-902.e2
Wang, Wei; Qin, Jiang-Jiang; Voruganti, Sukesh et al. (2014) The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models. Nat Commun 5:5086
Feng, Liang; Yao, Hang-Ping; Wang, Wei et al. (2014) Efficacy of anti-RON antibody Zt/g4-drug maytansinoid conjugation (Anti-RON ADC) as a novel therapeutics for targeted colorectal cancer therapy. Clin Cancer Res 20:6045-58
Yao, Hang-Ping; Zhuang, Chun-Mei; Zhou, Yong-Qing et al. (2013) Oncogenic variant RON160 expression in breast cancer and its potential as a therapeutic target by small molecule tyrosine kinase inhibitor. Curr Cancer Drug Targets 13:686-97

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