Colorectal cancer (CRC) is a malignant disease that affects millions of people around the world. The major cause of patient death is by tumor metastasis. Thus, studying CRC metastasis is critically important not only for understanding mechanisms of tumor malignancy, but also for developing tools for early diagnosis and effective treatment. Metastasis of CRC emerges from multiple genetic alterations and cellular disorganization. It occurs in a phase of tumor progression by metastatic variant cells that possess invasive activities characterized by increased cell migration, tissue invasion, and organ colonization. Despite intensive studies, our knowledge about the nature of invasive cells and the mechanisms underlying their origination is still limited. Recent studies using DNA microarray analysis have revealed that the proclivity of CRC metastasis is acquired early during multistage tumorigenesis. It is manifested only at late stages aided with additional genetic aberrations or cellular disorganization. During the study of CRC progression towards malignancy, we found that splicing variants of the RON receptor tyrosine kinase, such as oncogenic RON160, play a critical role in priming CRC cells with metastatic capability. Increased RON160 expression in colonic cells not only mediates cell transformation, but also promotes malignant metastasis. Thus, RON160 seems to act as a regulated metastasis-promoting switch in CRC cells. The goal of this project is to determine the signaling mechanisms by which oncogenic RON variants regulate metastatic phenotypes of CRC cells. We believe that malignancy acquired by metastatic variants of CRC cells is determined by metastasis-related proteins including oncogenic RON160. We hypothesize that splicing RON variants, such as oncogenic RON160, have the priming effect on CRC cells resulting in increased metastatic capabilities. In other words, metastatic potential is driven by oncogenic RON variants that initiate and activate cellular motile/invasive machinery leading to metastatic processes. To test this hypothesis, our studies will focus on following three specific aims: 1) To study how oncogenic RON160 is expressed in primary and metastatic CRC samples and its role in priming CRC cells into highly malignant variants;2) To determine the roles of RON160-activated signaling proteins and underlying mechanisms required for malignant conversion of CRC cells;and 3) To validate RON160 as a therapeutical target using monoclonal antibodies (mAbs) that exhibit growth-inhibitory and apoptotic effects on CRC cells. This work is important for the following reasons. First, it will determine the importance of RON160 in the progression of CRC cells towards malignancy. Second, it will facilitate our understanding of mechanisms underlying CRC metastasis. Finally, this work may identify novel targets for drug development to treat metastatic CRC. PUBLIC HEALTH RELEVANE: Metastasis of colon cancer is the ultimate cause of patient death. Currently, our knowledge about tumor metastasis is very limited, which reflects the lack of effective treatment for this deadly disease at clinical practice. Thus, understanding how colon cancer metastasizes is critically important. The project in this grant application is to determine the role of a cellular protein called RON in colon cancer metastasis. It is believed that such studies will help to determine mechanisms underlying colon cancer metastasis, to identify novel metastatic markers for early diagnosis, and to develop new drugs to treat patients with metastatic colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA091980-10
Application #
8234137
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Ault, Grace S
Project Start
2001-07-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$264,092
Indirect Cost
$86,252
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
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
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
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
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
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
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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