Research into Cachexia Seeks Treatment for Muscle-wasting Condition
Rodney Infante, M.D., Ph.D., Assistant Professor of Internal Medicine, Division of Digestive & Liver Diseases
As an M.D./Ph.D. student at UT Southwestern, Rodney Infante, M.D., Ph.D., was struck by the plight of the 30-50% of solid tumor patients who suffer from cachexia. Not only was their quality of life seriously diminished by rapid weight loss and muscle wasting, but they were often deemed ineligible for standard-of-care treatments, adding insult to injury. Since no one understood what causes cachexia, Dr. Infante decided to tackle it. Less than 10 years later, he is close to beginning a phase 1 trial on a possible solution.
Over the past few years, Dr. Infante’s research group has identified several influential molecules that are secreted from tumors or their associated inflammation. These cytokines can enter the bloodstream and influence other tissues, exacerbating the problem. One such cytokine is leukemia inhibitory factor (LIF), a member of the IL-6 family of cytokines. Dr. Infante’s group found that LIF is secreted from colon cancer cell lines and associated inflammation. It has also been linked to pancreatic cancer, lung adenocarcinoma, and renal cancers, which are often associated with cachexia.
Using purified LIF, Dr. Infante and his group found that they could induce cachexia in animals and study it without the confounding influence of cancer. What they learned is that LIF activates triglyceride lipolysis in adipocytes via the JAK/STAT3 signaling pathway. It also alters the expression of other cytokines such as IL-6 and leptin. Together, these changes affect the JAK/STAT3 pathway in the hypothalamus, which can cause an anorexic-like phenotype, adding to the patient’s weight loss. (Of note, in some patients, a countermeasure seems to dominate initially, with the body trying to counteract its increased lipolysis with an increased appetite.)
To fight cachexia, Dr. Infante knew they would need a molecule that can inhibit multiple cytokines, so his team started investigating JAK inhibitors, several of which are approved for use for rheumatoid arthritis and irritable bowel syndrome. In tissue and animal studies, the group found several potent candidates, and they are now collaborating with the maker of one drug to begin a phase 1 trial at UT Southwestern.
“No one person can do all of this,” said Dr. Infante. “I work very closely with oncologist Puneeth Iyengar. Together, we’ve created a database of cancer patients with and without cachexia. By looking for differences, we find clues to pursue in our preclinical research so that we aren’t just going from bench to bedside, but also bedside to bench.”
For his work on cachexia, Dr. Infante received a Career Award for Medical Scientists in 2019 from the Burroughs Wellcome Fund, providing him with $700,000 of research funding over five years. While learning about the mechanisms of cachexia, he also hopes to gain insights into an opposing problem – obesity.