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. In collaboration with Albert Baldwin, PhD, Associate Director of the Lineberger Comprehensive Cancer Center, and Ashley Wysong, a Howard Hughes Medical Institute Fellow, selective NF-κB inhibitors were used to reduce the inflammatory cascade that contributes to cancer cachexia. In a well-established animal model of cancer cachexia, two selective NFκB 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 addition, Ashley Wysong was able to collaborate with Monte Willis, MD, PhD, Assistant Professor in Pathology & Laboratory Medicine, to determine the cardiac effects of cachexia in this animal model. Their studies demonstrated that the function and structure of the heart were profoundly affected in a detrimental way in animals with cancer cachexia. The use of selective NFκB inhibitors was able to reverse these effects. 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.

In an effort to better define cancer cachexia, the metabolic profile was determined in an animal model using a new technology called 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 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. 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.

With collaborator Denis Guttridge, Associate Professor at Ohio State University, we published findings on the effects of chemotherapy on muscle atrophy. A commonly used chemotherapeutic agent, Cisplatin, was found to induce atrophy in both muscles and myotubule cultures, suggesting that a side effect of cancer treatment may be regulation of muscle wasting, and that this may be mediated via the NFκB signaling pathway.

Michael Stadler, MD (PGY3), who was awarded an American Academy of Otolaryngology – Head & Neck Surgery Resident Research grant, completed work on the effect of toll-like receptor 4 function on the anti-tumor response of using an allogeneic granulocyte monocyte – colony stimulating factor (GM-CSF) secreting HER-2/neu expressing whole tumor cell vaccine. Mitchell Gore, MD, PhD (PGY3) 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, especially PI3-AKT pathway.