The Last Illness
As if being diagnosed with advanced cancer or COPD was not bad enough news, patients with these hardcore diseases face the risk of also being afflicted with an illness that disrupts their appetite and metabolism which eventually leads to body mass loss and can lead to their death. This disease is called ‘cachexia’ and it was coined as ‘The Last Illness” in Nature’s Feature Report on the disease written by Carrie Lok.
Some Diseases associated with Cachexia
It is a wasting disease marked by great weight and muscle loss.
In the article, Susan McClement, a palliative-care researcher brings up her experiences with patient family members who cannot bear to see their loved ones become emaciated. One man, whose wife had metastatic breast cancer, resorted to force feeding her, pinching her nose and slipping spoonfuls of food whenever she opened her mouth. He was convinced it would give her energy to fight cancer. Sadly, she died a few weeks later. McClement found that these family members who fight to feed their ailed loved one feel regret, “They said, ‘You know, if I could do it over again, I would have spent much less time fighting about tapioca pudding and much more time telling my wife that I loved her.’”
“I would have spent much less time fighting about tapioca pudding and much more time telling my wife that I loved her”
The word cachexia is derived from the Greek kakos and hexis, meaning ‘bad condition’. This metabolic disorder that affects some 9 million people worldwide, with as many as 80% of people with advanced cancer, typically involved these main traits: extreme weight and muscle loss increased difficulty of making routine activities, increases risks of deadly complications like infection. A thing that shocks most relatives of patients with the disease is that nutrition and adding calories would not reverse their cachexia. McClement noted that the disorder then becomes a visual confirmation that their family member is sick and is not going to get better. Seen in the last stages of almost every major chronic illness, it is often overlooked by physicians and researchers who were more focused on treating the primary disease.
Who does Cachexia affect?
- 16–42% of people with heart failure
- 30% with chronic obstructive pulmonary disease
- up to 60% of people who have kidney disease
- Kills up to ⅓ of Cancer Patients
Basic research has allowed scientists to gain insight to the inner-workings of the now distinct, technically treatable condition. Cachexia was found to be driven by inflammation and metabolic imbalances, so this has generated drug targets. “Now we have quite a number of powerful options to test,”says Stefan Anker, a cardiologist and cachexia specialist at the University Medical Center Göttingen in Germany. However, some high-profile clinical trials in the past 2 years have shown disappointing results. “I’m a little bit worried that if we don’t see a successful clinical trial in the next five years, the dollars from the pharmaceutical industry to develop a treatment will go somewhere else,” says Jose Garcia, a clinical researcher focused on wasting disorders at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas. “In my view, that would be a missed opportunity.”
Cachexia, “distinct & treatable”
- Driven by inflammation
- Marked by metabolic imbalances
- Medication to treat it is still undergoing clinical trial stages
In 2006, those in the field of cachexia now conclusively define it as a condition which includes a loss of 5% or more of body weight over 12 months and reduced muscle strength.
Physical Signs of Cachexia:
- A loss of 5% or more of body weight in 12 months
- Reduced muscle strength
It is unfortunately under-recognized by oncologists, says Egidio Del Fabbro, a palliative-care physician and researcher at Virginia Commonwealth University in Richmond because there are no standard guidelines for treatment.
While research for the cause of this has only begun in past decade thanks to funding from the US National Cancer Institute and some advocacy groups, there are hopes that a standard treatment can be made soon, especially as there is increased exposure and support to combat the disease with the creation of new international conferences and the new Journal of Cachexia, Sarcopenia and Muscle, which both have brought more attention to the field. Now that they understand the key mechanisms behind cachexia are the characteristics of increased breakdown of muscle protein and dampening of protein synthesis which leads to muscle loss, it’s led to insights that can help researchers develop new drugs.
2001 studies that jump-started the field identified genes that were more active in atrophying rodent muscles than in normal ones. They encode enzymes called E3 ubiquitin ligases and they are responsible for tagging proteins to destructions in the cell. Mice without these enzymes were resistant to muscle loss. Muscle cells only made more of these ligases when they were given certain inflammatory signals that came from tumors or from immune cells responding to cancer or other illness. The enzymes created abnormalities in apoptosis and in mitochondria, the energy-producing organelles, in muscle cells.
But it’s more than just a muscle disease: there are studies that have identified issues in the brain’s regulation of appetite and feeding, and how the liver might be contributing to energy imbalances in the body, where the body burns its own tissue to sustain itself. Researchers that looked at fat tissue, which also can waste away in cachexia, showed that inflammation and molecules made by tumors caused white fat cells to turn into brown ones, which burn more energy to generate more heat than white fat cells. What researchers are studying more currently are how tissues and organs (muscle, brain, fat, bone) are communicating with each other. Last December 2015, a paper published suggested that fat signalling could be involved in muscle atrophy. This has brought more representatives of biotechnology and pharmaceutical companies to cachexia meetings says Denis Guttridge, a cell biologist at the Ohio State University in Columbus, who organizes one such conference. “That’s exciting for a basic scientist like myself,” he says. “I can see the increase in the translational pipeline.”
Image from Cell.com
The biotech firm GTx of Memphis, Tennessee launched a 2 late-stage clinical trials of enobosarm in 2011. The molecule binds to the same receptor as testosterone, but only in muscle and bone, mimicking the hormone’s ability to stimulate muscle build-up without undesirable side effects. Though result from earlier studies looked promising, with the testees having increased lean body mass and improved physical function as measured by their speed at climbing stairs, the larger tests of the drug, completed in 2011, on those with advanced lung cancer showed the benefits in function disappeared. The firm abandoned their tests on muscle wasting and is testing larger doses of enoborarm to treat breast cancer.
Unpublished studies on those with lung cancer and cachexia tested a compound called anamorelin. It mimics ghrelin, an appetite-stimulating peptide hormone produced mainly by the stomach. A pharmaceutical company Helsinn in Lugano, Switzerland sponsored the trials, which reported that participants in the treatment group put on weight and muscle mass compared with those taking a placebo, but showed no difference in handgrip strength The company announced last December that the European Medicines Agency is reviewing its drug for approval.
clinical trial test issues
Researchers find that perhaps current trials are not going well is perhaps they are testing the wrong features of muscle use and the most clinically relevant measures of muscle function are not being used. “We don’t really know what is the best test for this,” says Garcia. “If you can climb up a set of stairs one second faster, what does that mean?” This confusion about trial design is a problem for the field, says Anker. “We need to reach consensus on endpoints and what to aim for in our treatments.” Another issue is that animal data on cachexia might not be translatable into humans.
Though some work has tried making a case that mechanisms found in rodents might be similar to those in humans by looking at human tissue samples, says Vickie Baracos, a clinical translational researcher in muscle wasting at the University of Alberta in Edmonton, Canada. “But held up to scrutiny, this clinical evidence is often rather sketchy.” There is also a lack of samples of tissue from cachexia patients. What can improve Cachexia research efforts: more human data and clinical samples. Baracos suggesting this can be done by collecting blood and muscle samples along the way. “A cachexia data repository with a biobank would sure be a great thing,” she says. There is also competition for funding and recognition with research for other diseases, says Anker.“Cachexia is competing for internal resources within big companies, fighting with cancer, cardiology,” he says.
Garcia says an effective treatment would be transformative, as it may stir physicians to speak about cachexia to patents and their families about the symptoms because without the tools to address the disease, many doctors will not discuss it and it can be distressing for patients and their families to not know they do have it. McClement interviewed more families of people with cachexia and she hopes to find ways to better inform them about the condition. She wants to help them cope. These psychosocial interventions are important in the absence of pharmacological ones that many so rely on.
A New Hope: Fn14 Expression and the 28-member International Research Crew
This absence, however, does not mean there are deficits in the gained knowledge from recent studies. After all, it’s only been a decade since the scientific has brought their greater attention to the importance of cachexia in life-debilitating diseases.
In 2015, La Trobe University scientists have discovered a cause of cachexia.
Fn14, a receptor on a cell’s membrane which is often present on cancer cells, can cause cachexia. Its normally seen to aid the development of and repair of tissue and is turned on and off only for those specific moments it’s needed. Cancer cells express Fn14 continuously, signalling the rest of the body to attribute to muscle wasting.
Work on developing drugs to potentially end the disease has already begun. A big number of people with cancer – between 50 to 80 per cent of those with solid tumours – suffer from the condition. In advanced cachexia, cancer treatment is often stopped due to a person’s emaciated state.
While it was previously thought that weight-loss in cancer was due to tumor spread and tumor consumption of the body as well as appetite and nutritional complications that cause the body to waste away. However, in November 2015, the life sciences journal Cell published game-changing research led by the Department of Biochemistry and Genetics at the La Trobe Institute for Molecular Science (LIMS).
The inhibition of Fn14 could stop cachexia, regardless of the presence of a tumor. Professor of Biochemistry, Nick Hoogenraad, said “These findings, based on about a decade of research, could translate into huge benefits for those fighting serious illness and the potential for effective treatment is now much closer to reality. “If we can arrest cachexia it will give people extra time, improved quality of life, make them stronger and allow for therapy to continue.
“This is a very significant development.” Lead author of the Cell paper, Dr. Amelia Johnston, said that Fn14 has been known to be involved in cancer, but it was a surprise to us that it caused the wasting condition.
“Our treatment is an ‘antibody’ directed against Fn14, and because antibodies are very specific to their target, this means treatment is less likely to come with the unwanted side effects of other therapies such as many chemotherapy drugs,” says Johnston.
See Dr. Amelia Johnston explain the feat in La Trobe’s Big Fat Idea
“Cachexia: Wasting of the body in cancer patients”
This discovery and treatment with ‘antibody’ therapy that blocked cachexia also slowed the growth of tumors. They are now preparing for human trials. “Our findings are a positive step in the right direction for developing a treatment for cancer-cachexia. We are currently converting the antibody therapy into a treatment appropriate to trial in humans,” said Dr. Johnston.
“This is being done in collaboration with scientists at the Olivia Newton-John Cancer Research Institute. After we have made an equivalent therapy for human use, clinical trials would be the next step.” It was Dr. Kate Murphy, University of Melbourne collaborator, that helped characterize the laboratory model of the disease used in the research. Murphy says, ‘Cancer cachexia is such a serious complication of cancer and affects patients’ quality of life and ability to undergo punishing chemotherapy treatments. There is no treatment for cachexia, so the ability to develop one would be a huge step forward.’ This 28-member international research team included Professor Nick Hoogenraad, Dr. Amelia Johnston and Laura Jenkinson, La Trobe University; Associate Professor John Silke, Walter and Eliza Hall Institute; Professor Gordon Lynch and Dr. Kate Murphy, University of Melbourne; and scientists from Melbourne’s Baker Institute. International collaborators are from the Universities of Lausanne and Zürich, Switzerland; and Harvard, MIT and Biogen Idec in the United States. The project was originally funded by the Co-operative Research Centre for Biomarker Translation and is currently funded by the NHMRC.
Although two different diseases, cachexia and cancer share the same requirement of proper expression via microenvironment to properly continue their destruction. The idea of cancer needing a proper environment to thrive is seen in Mina J. Bissell, Ph.D’s studies, whose research that has won the prestigious 2016 E.B. Wilson Medal, has amazingly shown this feat. She explains it in the TED talk below:
#TributeTuesday Congratulations to our collaborator Mina J. Bissell, PhD who was awarded the 2016 E.B. Wilson Medal (the highest scientific honor from the American Society for Cell Biology)!!! Many recent #Nobel laureates were also Wilson Medal awardees including Randy Schekman, Roger Tsien, Avram Hershko, and Elizabeth Blackburn. Prof. Bissell was one of the earliest to study the #tumor #microenvironment (TME). The critical importance of the TME was demonstrated in her 1984 #Nature paper (PMID: 6203040). In a nutshell, #oncogenes are not sufficient to cause #cancer… You also need a permissive microenvironment (often an inflamed one). #contextiseverything An analogy is the seed and soil concept… It is virtually impossible to grow a cactus in a North Carolina swamp, duh! She presented a summary of her work at a brilliant #TEDMED talk in 2012 (I highly recommend all young scientists watch this!!!): http://bit.ly/1V8qEo0 #cancerresearch #cancer #oncology #breastcancer #medicine #oncogene #science #laboratory #TEDtalk #confocalmicroscopy #microscope #biotechnology #startup #biotechstartup #research #womeninscience #biology #cellbiology #instascience (Photo Credit: CC BY-NC-ND 2.0)
With these developments against cachexia will come possibilities in treating the disease. It will allow patients to thrive longer, to enjoy fine meals, and will hopefully give them time to build a tolerant system strong enough to endure more treatment, but more than anything, allow to them to enjoy the time they do have left with ones they love without anymore loss and ache they already face.
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