Targeting Sulfiredoxin in Colorectal Cancer
Abstract
Scientific Objective and Rationale: Colorectal cancer is the third most commonly diagnosed cancer in U.S. Veterans and worldwide. One of the major causes of colorectal cancer mortality is the spreading of cancer cells from the primary tumor site to distant organs, a process known as cancer cell invasion and metastasis. The long-term goal of my research is to identify molecular drivers and indicators of cancer cell invasion and metastasis and to further understand their function mechanisms to develop effective ways of targeted cancer therapy. Sulfiredoxin is a novel redox enzyme that has a critical role of promoting the metastasis of colorectal cancer. We have demonstrated that Srx enhances the epithelial growth factor receptor signaling and identified a novel small molecule inhibitor of Sulfiredoxin. In this project, we will study molecular mechanisms by which Sulfiredoxin promotes cancer cell invasion and metastasis and evaluate the efficacy of Srx inhibitor to block colorectal cancer tumorigenesis and metastasis using cell culture as well as mouse models. My Career Goals in Cancer Research: I have a strong background in medicine, cell signaling, and cancer cell biology, and have received multiple awards including several Scholar-in-Training awards from the American Association for Cancer Research, the National Cancer Institute (NCI) Director s Intramural Innovation award, Leukemia and Lymphoma postdoctoral fellowship, the NCI s Pathway to Independence award, etc. My career goal is to become an expert in the field of understanding cancer biology to develop novel strategies for the treatment of metastatic colorectal cancer. This Career Development Award provides me an opportunity of establishing and maintaining interdisciplinary collaborations with chemist, computational biologist, and clinicians; it also provides mechanistic data for future grant applications, translational studies, and support for presenting at national research meetings and workshops. By the end of the award, I will have obtained significant data and published manuscripts in colorectal cancer research, which will facilitate and accelerate me to become a leader in this field. Clinic Application: Our proposed studies of understanding the mechanism of Sulfiredoxin to promote cancer cell invasion and metastasis are essential for future development of therapeutics for metastatic colorectal cancer. The activation of epidermal growth factor receptor (EGFR) signaling plays an essential role in cell transformation, growth, and progression of many types of cancer including colorectal cancer. Monoclonal antibodies targeting the extracellular domain of EGFR, such as cetuximab and panitumumab, are used in clinic to treat metastatic colorectal cancer. However, there is a significant portion of patients that do not respond well to anti-EGFR therapy. Sulfiredoxin is preferentially expressed in advanced colorectal cancer patients, and its expression enhances the EGFR signaling pathway. Therefore, understanding the function of Sulfiredoxin in these signaling pathways may provide significant insights on the drug resistance of colorectal cancer cells. The test of the efficacy of the novel small molecule inhibitor of Sulfiredoxin in mouse models may pave the way for its subsequent translational application in patients. Our ultimate goal is to identify small molecules that can be used for the treatment of metastatic colorectal cancer in patients. Military Relevance: Due to risk factors such as post-mission stress, environmental exposure, and genetic susceptibility, the incidence of colorectal cancer in Veterans is very high and ranked as the third most commonly diagnosed cancer. Nearly 50% of patients initially diagnosed with colorectal cancer will develop distal metastases, and the 5-year survival rate of patients with metastasis is only 6%. The most recent data of year 2012 from the Veterans Affairs cancer registry reveal an average colorectal can
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610203
Entities
People
- Qiou Wei
Organizations
- United States Army
- University of Kentucky