|Duane Compton, Ph.D. (right)||Ethan Dmitrovsky, M.D., Provost|
|Geisel School of Medicine/Dartmouth||MD Anderson
Rexinoid Therapy for Lung Cancer Prevention
Lung cancer is the leading cause of cancer deaths for men and women. Despite current strategies to treat lung cancer only a small minority of patients are now cured, thus there is a pressing need to find innovative ways to treat or prevent lung cancer. This is the subject of this program between two highly interactive faculty members at MD Anderson Cancer Center and Dartmouth Medical School (Drs. Ethan Dmitrovsky and Duane Compton).
This team has a strong track-record of working productively together in lung cancer research. They embrace the Waxman Foundation's emphasis on interdisciplinary collaborations. This program takes advantage of the fact that many cancer-causing mutations and activated oncogenes are already known to exist in lung cancer and some of the most common ones lead to chromosome instability. These, in turn, activate what is known as the DNA damage checkpoint that is not only the first line of defense against DNA damage by carcinogens, but also necessary for tumors to tolerate the genetic damage caused by these cancer-causing mutations or activated oncogenes. This program has already made substantial progress in understanding the consequence of regulating this DNA damage response mechanism.
One outcome of this program is the observation that targeting Chk1, a key checkpoint protein, can overcome addiction to an oncogene that is frequently found upregulated in lung cancer and correlates with poor prognosis. Targeting Chk1 caused lung cancers to be substantially repressed in a clinically relevant mouse lung cancer model. Another is that their team uncovered a novel therapeutic and preventive target that affects chromosome stability and causes death of lung cancer cells and also prevents lung cancers from forming in model systems. A new finding by this group that is the topic of this application is that lung cancer cells with mutations in the RAS proto-oncogene are sensitive to inactivation of the same targets.
There is currently no therapy available for RAS mutant lung cancer cases, which make up about 30 percent of lung cancers. Given the public health benefits that would come from a deeper understanding of these checkpoint arrest mechanisms and from targeting these pathways, we are eager to pursue the studies addressed in this program.