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|Ref Type||Journal Article|
|Authors||Buchanan FG, Holla V, Katkuri S, Matta P, DuBois RN|
|Title||Targeting cyclooxygenase-2 and the epidermal growth factor receptor for the prevention and treatment of intestinal cancer.|
|Date||2007 Oct 1|
|Abstract Text||Clinical and animal studies indicate a role for cyclooxygenase-2 (COX-2) and the epidermal growth factor receptor (EGFR) in the development and progression of intestinal polyps and cancers. Although this combination of enzyme inhibition has shown synergy in intestinal polyp and tumor models, the exact mechanism for these effects remains undefined. Therefore, we sought to define the molecular mechanisms through which this process occurs. We observed a significant reduction in the number and size of small intestinal polyps in APC(min+/-) mice treated with either celecoxib (a selective COX-2 inhibitor) or erlotinib (Tarceva, an EGFR inhibitor). However, in combination, there was an overall prevention in the formation of polyps by over 96%. Furthermore, we observed a 70% reduction of colorectal xenograft tumors in mice treated with the combination and microarray analysis revealed genes involved in cell cycle progression were negatively regulated. Although we did not observe significant changes in mRNAs of genes with known apoptotic function, there was a significant increase of apoptosis in tumors from animals treated with the combination. The inhibition of EGFR also induced the down-regulation of COX-2 and further inhibited prostaglandin E2 formation. We observed similar effects on the prevention of intestinal adenomas and reduction of xenograft tumor volume when nonselective COX inhibitors were used in combination with erlotinib. Together, these findings suggest that the inhibition of both COX-2 and EGFR may provide a better therapeutic strategy than either single agent through a combination of decreased cellular proliferation and prostaglandin signaling as well as increased apoptosis.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Celecoxib + Interferon alpha-2b + Rintatolimod||Celecoxib Interferon alpha-2b Rintatolimod||0||1|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Celecoxib||Celebra||Celebra (celecoxib) is a COX-2 inhibitor FDA approved as an anti-inflammatory agent and for colorectal polyp reduction (FDA.gov) and also promotes apoptosis of tumor cells (PMID: 17909047).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|APC inact mut||colorectal cancer||sensitive||Celecoxib||Preclinical||Actionable||In a preclinical study, APC inactivating mutant mouse models of colon cancer had reduced polyp formation after treatment with Celebra (celecoxib) (PMID: 17909047).||17909047|
|APC inact mut||colorectal cancer||sensitive||Erlotinib + Ibuprofen||Preclinical - Cell line xenograft||Actionable||In a preclinical study, ibuprofen, in combination with Tarceva (erlotinib), demonstrated efficacy in reducing tumor number and volume in APC inactivating mutant mice and in cell line xenograft models of colorectal cancer (PMID: 17909047).||17909047|
|APC inact mut||colorectal cancer||sensitive||Celecoxib + Erlotinib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Celebra (celecoxib), in combination with Tarceva (erlotinib), demonstrated efficacy in reducing tumor number and volume in APC inactivating mutant mice and in human colorectal cancer cell line xenograft models (PMID: 17909047).||17909047|