Grants and Contracts Details
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer death in both men and women. Due to the essential role of epithelial growth factor receptor (EGFR) in CRC, anti-EGFR monoclonal antibodies, such as cetuximab, are frequently used in clinic to treat patients with metastatic CRC. However, a significant portion of patients do not respond well to anti-EGFR treatment, which urges further understanding of EGFR-activating mechanism and development of reagents for better targeting. Sulfiredoxin (Srx) is a novel oxidoreductase that restores the peroxidase activity of peroxiredoxin (Prx) to maintain cellular redox balance and a regulator of redox-related cellular signaling. We have published substantial amounts of data indicating that abnormally high expression of Srx in several types of human cancer promotes tumor growth and increases their malignancy. However, molecular mechanisms by which Srx promotes CRC tumorigenesis and cancer progression have not been fully understood, and the value of targeting Srx in cancer therapy has yet to be determined. In this proposal we will complete the following specific aims: (1) to demonstrate that the Srx-Prx4 axis is required for colon tumorigenesis in vivo; (2) to investigate the detailed mechanism by which the Srx-Prx4 axis promotes colon tumorigenesis and cancer progression; (3) to demonstrate that targeted disruption of the Srx-Prx4 axis by a novel small molecule inhibitor of Srx, ISO-1, inhibits patient-derived xenograft (PDX) growth and abolishes PDX-induced metastasis in mouse. Successful completion of the proposed work will reveal a previously neglected function of redox regulators in tumorigenesis and cancer progression; provide in-depth understanding of a novel mechanism of oncogenic EGFR activation by receptor post-translational modification; ascertain new insights to understand why some cancer patients are resistant to anti-EGFR therapy. Investigating the efficacy of ISO-1 in mouse PDX model may pave the way for the development of more specific, potent small molecule inhibitors to be used for the treatment of CRC in patients.
|Effective start/end date||1/1/18 → 12/31/23|
- National Cancer Institute: $1,718,234.00
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