Action to Cure Kidney Cancer recently awarded a $30,000 grant to the University of Texas Southwestern (UTSW) to support the work of a young scientist, Sarah Huen, for a year in kidney cancer research, specifically in cachexia. Our intention is to interest young researchers in initiating work in kidney cancer and hopefully continuing their future work in RCC. We chose UTSW since it is the home to one of the two kidney cancer SPORES (Specialized Programs of Research Excellence), established by the National Cancer Institute in order to advance organ specific research. The presence of a SPORE at UTSW takes advantage of a strong support network that can provide guidance to young researchers.

UTSW went through a rigorous selection process before choosing Sarah Huen as an ACKC Fellow. Sarah is both a nephrologist and a researcher, having received her medical degree from Northwestern University and her Ph.D., in Investigative Medicine from Yale University. She has also done postdoctoral work in Immunology at Yale. Her expertise in inflammatory metabolism will be applied to her work on cachexia, which is a syndrome in which patients with cancer and other diseases experience wasting of muscle mass and fat tissue. It is estimated that for cancer patients who die from their disease, 30% do so due to cachexia, which can be present in localized as well as metastatic disease. Ketones are molecules, produced in the liver, that can serve as an alternative fuel source to glucose. They have a protective value vis-à-vis cachexia. In the study that has been funded by ACKC, Sarah will test the hypothesis that ketones can protect kidney cancer models from cachexia.

The following is a summary of ACKC’s interview with Sarah.

As we said above, ketones provide the body’s cells with an alternative to glucose and offer a protective response when someone is fasting. Recent research suggests that ketone production can protect against cancer-related cachexia. What is not known is whether ketones themselves are a driving force against the development of cachexia, or are simply a byproduct of the fasting mechanism. One of the questions that Sarah will look into is what parts of the metabolic program that is activated in response to what’s called the cachexia/anorexia syndrome are protective and what parts cause harm and need to be reversed.

Cachexia occurs not only in cancer but also in other diseases and in infections. Its mechanism of action may be different in these disparate settings and may require different responses. Little work has heretofore been done in cachexia in kidney cancer, however, one study at UCLA surprisingly found that 15% of patients with localized, non-metastatic RCC actually had cachexia-like symptoms such as anorexia, malaise, and weight loss, which were associated with worse prognosis, recurrence of their disease, and decreased survival. There may also be something in the kidney cancer tumor that interferes with the efficient production of ketones. This will be a focus of investigation.

Most cancer-related studies in cachexia have been done in pancreas, lung, and colon cancers, so this project provides an opportunity to study the uniqueness of cachexia in an RCC environment and whether there is a therapeutic potential for enhancing ketone production through diet or medication. It is known that cachexia itself cannot be reversed by conventional nutrition support.

PPAR-alpha is a transcription factor that regulates energy homeostasis, or the ability of the body to maintain equilibrium despite environmental changes. It regulates the enzymes that produce ketones. Sarah is very interested in exploring how ketone production affects survival, organ damage, and cachexia in cancer and bacterial infections, and, in this case, kidney cancer. She will look at changes in inflammatory markers, based on PPAR-alpha treatments and what roles inflammation plays in tumorigenesis.

If one has a patient, with cancer and with cancer-related cachexia, who undergoes a successful treatment for the cancer, the cachexia goes away, as it does when present during infection and the infection is eradicated. If a patient has stable disease, the associated cachexia is also stable. If the cancer progresses, so does the cachexia, threatening survival at which time treatment for cachexia becomes critical.

People with kidney disease also have a decreased immune system and are at increased risk of developing life-threatening infections. Cachexia in patients with cancer, infections and especially patients with end stage kidney disease is common. How cachexia syndromes develop, what is their difference among these patients and whether they can be treated similarly is still unknown. Sarah is a kidney doctor and is interested in changes in metabolism in patients with kidney-related diseases including kidney cancer. We are hopeful that her work will shed light on the etiology of cachexia in kidney cancer and its treatment.

Note: Interviewers: Jay Bitkower and Carol Gracco.