Reference Detail

Ref Type

Journal Article

PMID

(17909047)

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	67	19	2007 Oct 1	9380-8	Cancer Res

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Celecoxib	Celecoxib	2	5
Celecoxib + Interferon alpha-2b + Rintatolimod	Celecoxib Interferon alpha-2b Rintatolimod	0	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Celecoxib				Celecoxib is a COX-2 inhibitor that blocks inflammatory response and has anti-angiogenic and anti-proliferative activities (PMID: 31726219), which may lead to tumor growth inhibition (PMID: 17909047, PMID: 16740761).

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	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	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	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