Over 30% of US Veterans are obese, and over 25% also have diabetes. An under-appreciated consequence of the epidemic of obesity and type 2 diabetes is an increased risk of cancer. In the Veteran population, lung cancer remains the number one cause of cancer death. This tremendous burden of disease argues that we need to find new methods for treating lung cancer, either by preventing its occurrence or increasing the effectiveness of available therapies. The clinical association between diabetes and cancer raises the possibility that drugs developed for diabetes may be effective in cancer. This proposal aims to take advantage of the links between metabolic disease and cancer to develop new agents to increase the susceptibility of lung cancers to current therapies, and possibly to prevent the development of early stage lung cancer.

My proposal focuses on a gene called PPAR-gamma, which is the target of the anti-diabetic drug pioglitazone (Actos). My mentor's lab discovered this gene and showed that drugs like pioglitazone are able to combine with conventional lung cancer chemotherapy to increase their effectiveness in killing lung cancer cells in a dish and in models of lung cancer in lab mice. This combination has been tested in people, but the results are still not final. Early reports showed that the combination was not more effective, although this may due to the fact that these drugs cause fluid retention, which can accumulate around the lungs.

Recent work in my mentor's laboratory showed that the ability of this gene to control diabetes is more complicated than we previously thought. It appears that PPAR-gamma has two "switches" that control different aspects of its function. Drugs like Actos flip both switches, while new drugs that were developed by one of our collaborators only flip one of these switches. These drugs don't cause the fluid retention, which is controlled by the other switch.

I have explored whether these new drugs that only work on one switch would be able to sensitize lung cancer cells to conventional chemotherapy. Because these new drugs do not have many of the side effects of the older drugs, they may be better for treating lung cancer. We have shown that these drugs are as effective, and perhaps better, than the older drugs in treating lung cancer cells in a dish and in lab mice.

This proposal aims to identify the mechanism that allows these drugs to sensitize cancer cells. We propose to look at the changes in the genetic profile of cancer cells treated with these drugs to look for new candidates are responsible for increasing the sensitivity of these cells to chemotherapy. We will also look at these genes in human patients who have been treated with a combination of chemotherapy and Actos as well. We hope to identify key gene changes that may predict who might benefit from this kind of treatment. We are also taking a complementary approach, which looks at the proteins that interact with PPAR-gamma, as this adds to our understanding of the mechanism of these drugs. Finally, we have made a mouse model that lacks one of these switches, and we are planning to test whether this absence affects the development of lung cancer in mice that are predisposed to cancer. If we see a difference, this may suggest that we can use these drugs to prevent lung cancer in people.

I am a radiation oncologist who treats lung cancer patients at the Massachusetts General Hospital. I have done prior research studying a gene that controls the activation of other genes, much like PPAR-gamma. Given the huge burden of lung cancer in the Veteran and military population, I am interested in taking new approaches to try to improve the effectiveness of current treatment and to prevent the development of cancers. By looking at developments in the world of diabetes, I hope to find new pathways to translate into lung cancer treatment. I am fortunate to work with my mentor, Dr. Bruce Spiegelman, who is an international authority on diabetes and metabolic disease, who is also interested in finding new treatments for lung cancer.

This award will provide key support during a time when I am continuing my clinical work and also establishing data that will help me to start my own independent laboratory. It will also enable me travel to large meetings to present our work and to get new ideas on improving lung cancer treatment. My mentor and I have also arranged for a wide variety of courses, seminars, and meetings to ensure that I become a well-established scientist in the lung cancer field.

We are hopeful that this research will establish the mechanisms of action of these new drugs and provide an opportunity for new drug development in this pathway. We anticipate that this work will help identify markers of the patients who are most likely to benefit from these treatments. We hope that the relatively non-toxic nature of these drugs and their ability to be combined with other therapies will make them an attractive option in the treatment of lung cancer.