In the late 1980s, researchers led by Alfred L. Goldberg, PhD, first isolated the large protein complexes now called 26S proteasomes, which are the sites where most cellular proteins are degraded back to amino acids. Protein degradation by the proteasome pathway is critical in regulating many processes—especially cell growth—and, thus, its proper function is important in the development of certain malignancies. Consequently, some blood cancers (eg, multiple myeloma) can be successfully treated with the inhibitor of the proteasome, bortezomib, and other such inhibitors are in clinical trials. More recent work by Dr. Goldberg and collaborators has led to a promising understanding of the mechanisms of cachexia, one of the most persistently troublesome and heretofore untreatable symptoms of cancer. Dr. Goldberg, Professor of Cell Biology at Harvard Medical School, spoke to The ASCO Post about possible breakthroughs in understanding and treating cachexia.
Recent Insights
What have we learned over the past decade about cachexia that might help translate into treatment?
The fundamental and most debilitating aspect of cachexia is muscle atrophy, which we now know results from very specific biochemical changes in the muscle. It is not simply a nonspecific effect from not eating sufficient nutrients, resulting from anorexia often seen in patients, or physical inactivity. Instead, cachexia develops through a specific set of biochemical adaptations in the muscle, including a well-defined set of changes in gene transcription that lead to an acceleration of muscle protein breakdown.
In the past, cachexia was largely ignored both by the oncology community and investigators interested in muscle or metabolic regulation. The major new insights into this process have come from studies in animal models. There is now a consensus that in cancer cachexia and a variety of other catabolic states (from severe burns to cardiac or renal failure), muscles express a specific set of atrophy-associated genes, which we have named “atrogenes” because they are turned on or off similarly in many conditions when muscles atrophy. For example, atrogene expression may be seen in bed-ridden patients with unused muscles, cases of nerve injury, fasting or tumor-bearing animals, septic individuals, and so forth.
This common transcriptional program functions in muscles in a diversity of catabolic states to trigger muscle protein degradation and consequently the patient’s negative nitrogen balance. Although the factors signaling this response may vary in these different catabolic states (and there seem to be a number of cytokines that trigger the atrogene program in muscle), the consequences within the muscle are the same—an acceleration of protein breakdown, which leads to a loss of the contractile apparatus (and thus strength) and of mitochondria (and thus endurance).
We believe this process in muscle, though deleterious when prolonged, actually evolved as a helpful adaptation to fasting or disease. For example, before medicine had evolved to be truly helpful to the patients, the breakdown of dispensable muscle proteins provided the fasting or diseased individual with a source of amino acids to convert into glucose or for wound repair, which is especially valuable when the individual may be too sick to forage for food. But presently in chronic disease, the continual breakdown of muscle proteins is certainly undesirable in patients, and now a number of efforts are underway to develop therapies to reduce or turn off these degradative processes.
Myostatin and Activin A
In 2010, you were part of an Amgen team that published a study on cachexia in Cell.1 Can you describe how that work coincides with current studies?
I was only a consultant on that study, which was led by H.Q. Han, MD, PhD, who once was a student in my lab. His team has been investigating ways to reverse cachexia. Their studies and several other research efforts in the pharmaceutical industry build upon a key regulator of muscle size, called myostatin. More than 10 years ago, work by Se-Jin Lee, PhD, at Johns Hopkins University showed that myostatin is a factor normally produced by muscle that continually inhibits further muscle growth. Animals that lack myostatin have much more (up to twice as much) muscle mass. Conversely, excessive myostatin can induce a dramatic loss of muscle mass, which raises the obvious question: What is the physiologic role of myostatin or related polypeptides, both normally and in cachexia?
Is this line of scientific inquiry being actively looked at?
Using Dr. Lee’s work as a foundation, several companies are developing antagonists for myostatin or related TGF-family members that may be used to build up muscle in patients with cancer cachexia, bedridden patients, and perhaps in myopathies. This research is very promising, as illustrated by our paper,2 which showed that if an antagonist to myostatin can slow the process of cachexia in tumor-bearing mice or reverse the process completely, even in severely cachectic animals.
In tumor-bearing mice that had lost over 10% of body weight, a single injection of a soluble decoy receptor that mimics the receptor on the muscle, but is floating free in the circulation, was enough to reverse the loss of weight and strength. By soaking up the myostatin and related cytokines, this treatment prevented them from acting on the muscle and thus blocked the induction of atrogenes, the accelerated protein breakdown, and the loss of muscle mass. This beneficial effect was notable because the tumor continued to grow and release catabolic factors. It later became clear that the soluble receptor was not only soaking up myostatin but was actually binding a closely related molecule called activin A, which the intestinal tumor had been making in large amounts.
Activin A had been known for some time for its role in regulating the female menstrual cycle, but it also appears to be one of the cancer-released cachexia-inducers. In addition to its other normal functions, it is highly catabolic to muscle. The idea that tumors were releasing this cytokine and that it was catabolic to muscle had not been appreciated. There are a number of cancers that produce activin A in large amounts, so this is a significant finding that should stimulate appreciable future work.
Potential Clinical Impact
Did this team of researchers find anything that might influence clinical behavior down the line?
Yes, there was one dramatic finding. The studies of Han’s group showed that when the cachexia process is reversed and muscle builds up again, the tumor-bearing animals lived much longer even though tumor growth was unchanged.2 So, this is the first direct experimental evidence indicating the importance of cachexia in determining the host’s ability to withstand the impact of the cancer. Hopefully someday, in addition to treating the tumor, the oncologist will also be able to treat the host, because the cachexia itself appears to be highly deleterious and to affect the patient’s longevity. In other words, in many cases it appears to actually be the cachexia that causes death rather than the cancer itself.
In light of this and other work, is cachexia getting enough attention in the medical community?
Not yet in the medical community, but certainly there is growing interest among researchers. A growing number of academic investigators and a number of companies have finally recognized that cachexia is very damaging to patients on multiple levels in many disease states, and acknowledge a rationale for drug development. There is even a new specialized Journal of Cachexia, Sarcopenia and Muscle, and a Society for Sarcopenia, Cachexia and Wasting Disease that has annual meetings.
This area used to be just the province of nurses, nutritionists, and others interested in supportive care, but now there’s growing involvement from industry and basic investigators in efforts to fully understand the mechanisms behind cachexia. The ultimate goal is to develop anticachexia therapies that could be used together with chemotherapy, and would also have multiple applications in medicine aside from patients with cancer.
Closing Thoughts
Any last thoughts on the clinical issue of cachexia?
The recent insights discussed here and others are finally stimulating a great deal of interest in the cachectic process that had been, for the most part, ignored by cancer researchers and clinicians. Naturally, oncologists focus their efforts on tumor shrinkage or elimination; however, I think we’re getting a clear picture that building up the patient’s strength seems to better enable him to handle the challenges of cancer. Much remains to be learned about the metabolism of the tumor-bearing patient and the pathophysiologic mechanisms of cancer cachexia.
These promising myostatin-related therapies are now entering clinical trials, and I believe they will help tumor-bearing patients—not just by increasing muscular strength and thus improving quality of life, but also by enhancing the patient’s ability to withstand the disease process and the effects of cancer therapies through mechanisms we still do not understand. This important therapeutic opportunity has been generally ignored, largely because of a lack of understanding of the underlying biology. ■
Disclosure: Dr. Goldberg was a consultant to Amgen on the cachexia study discussed in this article.
References
1. Tisdale MJ: Reversing cachexia. Cell 142:511-512, 2010.
2. Zhou X, Wang JL, Lu J, et al: Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142:531-543, 2010.
