Matthew K. Topham M.D.

Recipient of the Kate McMullen Foundation /Joan’s Legacy Research Grant. Funded equally by Joan's Legacy and the Kate McMullen Foundation.

Lay Description

Recently, scientists found mutations in some lung adenocarcinomas and bronchioalveolar carcinomas that activate a tumor promoting receptor called EGFR. We found that these mutations in EGFR caused high expression of another protein called COX-2. The COX-2 protein can, in turn, activate EGFR, potentially creating a perpetual growth cycle. COX-2 also promotes inflammation, and in addition to increasing COX-2, mutant EGFR also causes expression of other pro-inflammatory proteins. Normally, inflammation is appropriate and helps healing, but too much inflammation can cause injury and even promote cancer. Our findings suggest that in tumors with mutant EGFR, COX-2 and inflammation contribute to tumor growth and maintenance. We propose to study the role of COX-2 and inflammation in tumors that have EGFR mutations. If we find that they contribute to tumor growth and maintenance, it might be possible to improve treatment of lung tumors with mutant EGFR by providing anti-inflammatory medications such as the COX-2 inhibitors aspirin, ibuprofen, or Celebrex.

Scientific Abstract

Epidermal growth factor receptor (EGFR) is linked to tumor development and progression through increased cell proliferation, survival, migration, and angiogenesis. Its activity is often abnormally high in many cancers and this correlates with a poor prognosis. The tumor-promoting properties of EGFR are largely due to its ability to activate proliferation and survival signaling pathways, but EGFR also promotes inflammation that might further facilitate tumorigenesis. Recently, mutations in EGFR have been discovered in lung adenocarcinomas that increase its activity. Transgenic models that express EGFR with these activating mutations develop adenocarcinomas and bronchioalveolar carcinomas that have associated inflammation. We hypothesize that these mutations in EGFR not only cause tumor growth through the canonical proliferation and survival signaling pathways, but also by inducing expression of inflammatory mediators that further promote tumorigenesis and metastasis. We propose that cyclooxygenase-2 (COX-2) and CXCL5/ENA-78 are important mediators of this inflammation. Using isografts and transgenic models, we plan to study whether these inflammatory mediators contribute to tumorigenesis in the context of activating EGFR mutations. Since our preliminary data point to an important role for COX-2, we also plan to test the effects of COX-2 inhibitors. Our experiments will help design rational therapies for tumors with abnormally active EGFR signaling.