With muscle-building treatment, mice live longer even as tumors grow

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With muscle-building treatment, mice live longer even as tumors grow

http://www.eurekalert.org/pub_releases/2010-08/cp-wmt081610.php

In the vast majority of patients with advanced cancer, their muscles will

gradually waste away for reasons that have never been well understood. Now,

researchers reporting in the August 20 issue of Cell, a Cell Press Publication,

have found some new clues and a way to reverse that process in mice. What's

more, animals with cancer that received the experimental treatment lived

significantly longer, even as their tumors continued to grow.

" This is the first demonstration that muscle mass plays a key role in cancer

survival, " said H.Q. Han of Amgen Research.

While it has long been recognized that this muscle wasting condition, known as

cachexia, affects advanced cancer patients' quality of life, Han explained, its

importance for survival had primarily been a matter of speculation. Nearly 30

percent of cancer-related deaths have been attributed to cachexia, but that was

based on correlative evidence only. That is, there has seemed to be a connection

in cancer patients between weight loss and mortality.

Still, cachexia had typically been considered a " multi-factorial " process with

many causes. " That would make it hard to target, " Han said. Indeed, few

therapeutic options are available and efforts to treat this aspect of the

disease haven't been top of mind. Given the new results, that could change.

The researchers suspected that a pathway known as ActRIIB might be involved.

ActRIIB is what's known as an activin type 2 receptor. There was evidence to

suggest that tumors secrete activin, such that circulating levels of the protein

rise in those with cancer. Activin is closely related to another protein, called

myostatin, which is known to be important in muscle. Animals lacking myostatin

or taking treatments that block it grow bigger muscles. There was some evidence

to suggest that activin blockers might have a similar effect.

Based on that hunch, the researchers treated mice with cancer and associated

cachexia with a recombinant and soluble version of the ActRIIB receptor

(sActRIIB), a kind of molecular " decoy " that potently inhibited both activin and

myostatin activity. That treatment reversed the animals' muscle loss and

prolonged their survival by several weeks on average. That was despite the fact

that the tumors appeared to be unaffected. The animals also kept losing fat and

still had high levels of inflammatory factors.

" In tumor-bearing mice with profound cachexia, blocking this pathway not only

prevents muscle wasting but completely reverses the loss of muscle, strength and

anorexia, " Han said. (Anorexia is another symptom of cachexia, but appetite

stimulants and nutritional supplements don't help much.)

The researchers also found something that had apparently gone unnoticed before.

Just as the skeletal muscles of mice with cancer withered away, so too did their

heart muscle. The ActRIIB inhibiting treatment completely reversed that too.

Han said that finding may point to an unappreciated role for heart atrophy in

muscle wasting conditions more broadly.

Further experimentation showed that the ActRIIB blockade prevented muscle

proteins from being marked for degradation and markedly stimulated muscle

stem-cell growth. Muscle stem cells were successfully activated even in muscle

that had lost 50 percent of its weight prior to treatment, Han said.

" This is the first indication that there may be a major medical benefit in

extending life span by combating cachexia, " Han said, emphasizing however that

there is a long way to go from preclinical studies in mice to clinical trials in

human patients.

Still, he added, " as drug discovery scientists, we are very excited by the

implications. This suggests a promising strategy for treating cachexia and

underscores the need for further investigation and translational research to

fully understand this pathway and explore the benefits of its antagonism. "

The researchers say it will be important to explore levels of myostatin and

other components of the ActRIIB pathway in various patient groups. " The

dramatic, reversible changes in body mass shown here emphasize the importance of

obtaining such information not only for understanding disease mechanisms but

also to provide a fuller rationale for anti-activin therapies, " they wrote.

" However, since the inhibition of ActRIIB signaling by sActRIIB induces growth

of normal muscle, this treatment is likely to be anabolic and help combat muscle

loss in many catabolic conditions, even if the wasting is not triggered by

excessive signaling by activin or related ligands of the ActRIIB pathway. "

Han says he and his colleagues hope the findings will renew interest among

cancer researchers and oncologists in cachexia. " Our results argue that blocking

the catabolic actions of tumors should be a major therapeutic objective, not

only to enhance quality of life but also to prolong survival, " he said.

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The researchers include Xiaolan Zhou, Amgen Research, Thousand Oaks, CA; Jin Lin

Wang, Amgen Research, Thousand Oaks, CA; Lu, Amgen Research, Thousand Oaks,

CA; Yanping Song, Amgen Research, Thousand Oaks, CA; S. Kwak, Amgen

Research, Thousand Oaks, CA; Qingsheng Jiao, Amgen Research, Thousand Oaks, CA;

Rosenfeld, Amgen Research, Thousand Oaks, CA; Qing Chen, Amgen Research,

Thousand Oaks, CA; Boone, Amgen Research, Thousand Oaks, CA; W.

Simonet, Amgen Research, Thousand Oaks, CA; L. Lacey, Amgen Research,

Thousand Oaks, CA; Alfred L. Goldberg,2 and H.Q. Han, Amgen Research, Thousand

Oaks, CA.