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Cyclooxygenase-2 (COX-2) is often highly expressed in epithelial malignancies and has an active role in tumor development. This involves transactivation of the epidermal growth factor receptor (EGFR) through E-prostanoid receptors. EGFR over-activity also increases COX-2 expression leading to a positive feedback loop.
Creating a COX-2 over-expressing transgenic mouse resulted in promotion colon tumor progression, but not initiation, and it does so, in part, by activating EGFR and Akt signaling pathways. Using a combination therapy of EGFR & COX-2 inhibition in colorectal cancer patients is currently being studied.
More than half of lung cancer cases in “never-smokers” have an activating oncogenic mutation of EGFR. Typically responsive to small molecule inhibitors as a first line therapy, eventually these tumors become resistant. Resistance has been reported to occur due to a second EGFR mutation that changes small molecule inhibitor binding characteristics thus restoring EGFR activity.
COX-2, typically induced at sites of inflammation and neoplasia, is found to be over-expressed in mice in response to EGFR over-activity. Both COX-2 over-expression and EGFR overactivity lead to increased IL-6/STAT3 signalling. Inhibition of IL-6 results in growth reduction in xenograft mouse models. Additionally, COX-2 is a transcriptional target of STAT3 signalling leading to another positive feedback loop.
We are currently investigating the presence of COX-2 over-expression in EGFR mutant "Never-Smokers", as a prelude to potential EGFR COX-2 inhibition therapy, in this subset of lung cancer patients.
Control of colorectal cancer needs to be tailored to its etiology. Unlike sporadic or inherited tumors, colitis–associated colon tumors do not require cyclooxygenase (COX) activity for progression, and non-steroidal anti-inflammatory drugs (NSAIDs) which prevent sporadic or inherited colon cancer do not prevent colitis-associated colon cancer. Myeloperoxidase (MPOx), an ancestor of the COX isoenzymes, is a determinant of colitis-associated colon tumors in ApcMin/+ mice. During experimentally induced colitis, inhibition of MPOx dampens colon tumor development. Acrolein, a by-product of MPOx catalysis, forms a covalent adduct with the phosphatase tensin homolog (PTEN) tumor suppressor and enhances the activity of the Akt kinase proto-oncogene in vitro and in vivo. Thus, MPOx may be an important determinant of diet and inflammation on colon cancer risk via its effect on endogenous exposure to oxidants and acrolein.
The same MPOx by products above have been found in the bowels of inflammatory bowel disease patients. They may be an important determinant of increased colorectal cancer risk in these patients. Especially as several studies have shown a severity correlation of colitis associated colorectal cancer with MPOx activity.
Additionally, stem cell therapy in inflammatory bowel disease models has shown, among other effects, a reduction in MPOx activity.
We are currently in the process of setting up a clinical trial targeting MPOx activity chemically or using stem cell therapy in IBD patients.
Adrenomedullin signalling affects growth, angiogenesis, apoptosis, & migration. Adrenomedullin over-expression has been reported in several malignancies potentially correlated with KRAS mutations. Downstream MEK activity has been reported to be central to its carcinogenic effects. However, MEK inhibition while initially effective leads to rapid emergence of resistance through EGFR and other ERBB receptor tyrosine kinase over-activity.
Little is known about Adrenomedullin's role in colorectal carcinogenesis or the signalling pathways involved. Would inhibition of the pathway upstream of MEK lead to a better & longer lasting inhibition?