Marion E. Couch, MD, PhD
Marion Everett Couch, MD, PhD, and her colleagues continue to work on the mechanisms of cancer cachexia syndrome, a profound wasting syndrome, which affects many patients with advanced stage head and neck cancer. Previous studies had defined the clinical profile of head and neck cancer patients suffering from this metabolic derangement. It is not merely starvation and it etiology is multifactorial. Work previously done by her group in a clinical trial used anti-inflammatory agents such as cyclo-oxygenase II inhibitors to reverse its effects. To further elucidate the role of inflammation in this syndrome, selective NF-kB inhibitors were used to reduce the inflammatory cascade that contributes to cancer cachexia. In a well-established animal model of cancer cachexia, two selective NFkB inhibitors were used after the induction of cancer cachexia to reverse the muscle wasting seen. They had no toxic side effects in this short-term trial, and they prolonged survival in the animals. In collaboration with Albert Baldwin, PhD, Associate Director of the Lineberger Comprehensive Cancer Center, Ashley Wysong was able to work with Monte Willis, MD, PhD, Assistant Professor in Pathology & Laboratory Medicine, to determine the cardiac effects of cachexia in this animal model. The use of selective and short term use of these NFkB inhibitors were able to reverse these effects without causing cardiac hypertrophy. These findings may contribute to better understanding of why patients do not tolerate therapy, either medical or surgical, when they are suffering from cancer cachexia. Their studies demonstrated for the first time that the function and structure of the heart were profoundly affected in a detrimental way in animals with cancer cachexia.
Dr. Scott Shadafar (PGY2) is extending these studies by looking at the effect of the muscle enhancing agent, Resveratrol, which is also a NFkB inhibitor, on cancer cachexia. He will use our well-established murine model to investigate the short term use on Resveratrol on muscle mass, body weight, NFkB inhibition, and cardiac function.
In collaboration with Dr. Thomas O’Connell, the Director of Metabolomics at UNC, an effort to better define cancer cachexia, the metabolic profile was determined in an animal model using Metabolomics. This is a platform that allows for the survey of 1,500 different metabolites using NMR spectroscopy. Cancer cachexia was found to be distinctly different from starvation and low glucose levels, high low density lipoprotein and very low density lipoprotein levels are seen in the serum. Based on the metabolic profiles, we had evidence that cachexia could be reversed with resection of the tumor. Tumor burden alone did not account for the metabolic perturbations either. These studies will help us determine the exact metabolic derangements that exist in this condition. This will aide in future research studies as we may better define those patients who truly have cancer cachexia. In addition, these findings can be used to create a panel of metabolic markers to better define this condition in animals and in patients with cancer cachexia. There is a clinical trial to collect serum from patients with and without cancer cachexia, and this work will be extended to other patient populations.
Mitchell Gore, MD, PhD (PGY4) was able to modulate the effects of cancer cachexia and tumor growth in an animal model by using toll-like receptor (TLR) 9 agonist and antagonists. He also looked at various pathways involved in muscle wasting during cancer cachexia, especially PI3-AKT pathway.