Science Editor

"Treating the symptoms" is not usually a compliment. But scientists from Amgen Inc. and Harvard Medical School have shown that in at least one case, treating the symptoms did a lot for their murine patients. Treating cancer-associated wasting, or cachexia, in mice allowed them to live longer, even as their tumors continued growing.

The studies "provide the first direct experimental evidence that preventing and reversing muscle loss can significantly prolong the life span of cachectic tumor-bearing animals even in conditions where tumor growth is not inhibited." Amgen researcher H.Q. Han told BioWorld Today. As such, the findings, which appear in the Aug. 20, 2010, issue of Cell, are "likely to influence treatment of cancer patients, and perhaps patients with other wasting syndromes, e.g. wasting syndromes associated with AIDS, chronic kidney disease or congestive heart failure."

Metastasis is the best-known actual cause of death for cancer patients. But, Han said, cachexia "is also believed to be major cause of cancer-related death, perhaps causing as many as 20 percent to 30 percent of all cancer deaths." But while cachexia, or the decay of the host tissues caused by cancer, has long been recognized as a quality-of-life issue for cancer patients, "its importance in determining host survival had at most been a matter of speculation."

Despite its medical significance, cancer cachexia treatments are few and far between – in part, Han said, "due to the lack of understanding of the mechanisms underlying the pathogenesis of cancer cachexia." But the results his team published in Cell begin to change that.

Han and his team focused their attention on activin A and its associated pathway because many types of tumors secrete large amounts of activin A, possibly to feed themselves. They found that forced overproduction of activin A in mice resulted in a lethal muscle wasting syndrome, and implantation of activin A-secreting human tumors in nude mice also led to the development of cachexia and muscle wasting

The authors tested a "decoy receptor" – activin type-2B receptor or ActRIIB – that is actually a receptor for both myostatin and activin A in the blood. The decoy mops up activin, preventing it from binding to cellular receptors. When the authors treated mice with xenografted tumors with the decoy receptor, at the first signs of wasting, they found that such animals quickly gained weight and strength. For a while, in fact, treated animals gained enough muscle to be noticeably heftier than tumor-free, untreated controls.

Even when treatment was started later, after the animals had already lost a good part of their body weight, the animals were able to catch up with control animals after treatment was started. In behavioral experiments, the authors found that the animals were stronger than controls once they had been treated.

Surprisingly, animals treated for cachexia also survived longer even though their tumors were not being treated. If treatment was initiated promptly, more than 80 percent of mice treated for cachexia survived at the point where all 20 untreated mice had died. Even with delayed treatment, more than half of animals were able to survive.

This despite the fact that the animals treated for wasting had tumors that were clearly not wasting away. They were as big as the tumors in untreated mice. The authors concluded that "the dramatic muscle sparing is clearly not due to elimination of the primary tumor."

Nor is it due to any effects on cytokine signaling. Though earlier studies had suggested that increased levels of cytokines such as interleukin-6 can trigger wasting in advanced cancer sufferers, Han and his team found no evidence that they played a role. In fact, when they infused animals with IL-6, they saw no effect on either body weight or muscle mass.

Instead, the decoy appeared to work by several mechanisms. It activated muscle stem cells, which allowed muscle cells to build back up; it prevented muscle atrophy, including breakdown of heart muscle; and it increased appetite, though the latter appears to be a minor factor.

Thousand Oaks, Calif.-based Amgen already has AMG745, which inhibits myostatin but not activin, in Phase I trials against cachexia. Han said that the team plans to keep doing translational research to see whether it's worth adding to the mix. "It will be clearly important to further investigate the ActRIIB pathway biology in . . . clinical settings."