Studying fruit flies, an international team led by Harvard Medical School researchers reports that it has uncovered one of the molecular roots of cachexia, a poorly understood and currently incurable muscle-wasting and fat-loss condition responsible for as many as one-third of cancer deaths.
The findings, published online Jan. 10 in Developmental Cell, suggest that existing cancer drugs called MEK inhibitors could provide a way to target cachexia independently of the cancer itself.
“By figuring out more about the genesis of cachexia, our work suggests researchers can focus on the host tissues to address this severe condition and gain more time to fight the tumor,” said the paper’s first author, former postdoctoral researcher in the lab of Norbert Perrimon at HMS and now a professor at Wuhan University in China.
The study also provides the first evidence in support of recent theories that cachexia arises from cross-talk between the tumor and the body.
“It’s quite satisfying to use our fly model to uncover how tumors signal to normal tissues, particularly since these mechanisms are likely to be highly relevant to devastating human conditions of organ wasting, such as cachexia,” said , the James Stillman Professor of Developmental Biology in the Blavatnik Institute at HMS and senior author of the paper.
“It’s a good feeling anytime we make discoveries that could lead to improvements in patients’ lives,” he said.
Digging up the roots
Cachexia afflicts up to 80 percent of patients with terminal cancer, as well as many people with AIDS, heart failure, chronic kidney disease and other conditions.
In addition to decimating fat cells and skeletal muscle, which leaves patients weak and emaciated, cachexia blunts the body’s response to chemotherapy and raises the likelihood that a cancer will prove fatal.
To date, doctors have been able to treat cancer cachexia only by defeating the tumor that triggers it. Recently, however, attention has turned toward addressing cachexia in its own right.
Efforts remain in the early stages. While experimental treatments can alleviate aspects of cachexia in some patients, such as improving muscle mass or stimulating appetite, effective therapies to prevent or slow the condition have remained elusive, according to the . Boosting calorie intake doesn’t help.
Scientists like Perrimon and Song believe that understanding how cachexia operates at a fundamental level will reveal ways to combat it and other organ-wasting conditions.
In 2015, the Perrimon lab created a fruit fly model of colon cancer. Unexpectedly, the flies developed cachexia-like symptoms, including weak muscles, fluid accumulation, high blood sugar and transparent bellies where fat had disappeared.
The researchers seized the opportunity to probe the origins of organ wasting.
In 2016, they that the flies’ tumors release ImpL2, a protein that stifles insulin signaling. The blunted signaling prevents muscle, fat and other cells from absorbing sugar from the blood, effectively starving peripheral tissues, said Perrimon.
In the new study, the researchers identified additional culprits.
They found that the flies’ tumors secrete two proteins that turbocharge MEK signaling, a common way messages get communicated from cell surfaces to cell nuclei.
The team found that one protein, Vn, stays local. By boosting MEK signals, it stimulates excessive cell proliferation that drives tumor growth.
The other protein, called Pvf1, travels farther away from the tumor. The researchers discovered that when it reaches the flies’ fat and muscle cells, it activates MEK signals and triggers the tissue breakdown characteristic of cachexia.
A handful of MEK inhibitors—drugs that suppress MEK signaling—have been approved by the FDA to treat melanoma. When the researchers treated fruit flies with one such inhibitor, it reduced the insects’ muscle and fat wasting.
Even when the researchers made the tumors resistant to the drug, the effects persisted. Suppressing MEK in the flies’ normal tissues—without affecting the tumor itself—was enough to halt the wasting and extend the flies’ longevity.
Beyond the fly
Together, the studies challenge the traditional views of the causes underlying cachexia, said Song. According to one prevailing model, the tumor absorbs all available nutrients, causing malnutrition; according to another, the body’s immune response to the tumor suppresses healthy tissue function and leads to wasting. The new findings, Song explained, suggest instead that the proteins secreted by the tumors cause wasting directly.
The ultimate proof, of course, will lie in how well the team’s findings translate to humans.
Evolutionary similarities between flies and humans give the researchers confidence that the molecular players they identified will have medical relevance.
“All the proteins we studied are highly conserved from flies to mammals, including humans,” said Song. “We think our discoveries will prove universal.”
Wei and colleagues are now validating their findings in additional animal models and in human tumor samples, including pancreatic cancer—the cancer that most often leads to cachexia—as well as colon, lung and stomach cancers.
The team is also hunting for additional cachexia contributors, since MEK inhibition didn’t fully reverse the wasting.
“All these complicated diseases have multiple pathogenic factors,” said Song.
There will also be clinical obstacles to tackle if clinical trials explore MEK inhibitors as a cachexia treatment rather than as a cancer therapy in people. For instance, the drugs can have toxic side effects.
Most important, Song said, is the novel concept emerging from the study, the notion that protecting against the tumor’s “cachectic attack” may preserve patients’ quality of life and buy more time to treat the cancer itself.
“It’s like what is mentioned in The Art of War,” said Song. “Ancient fighters first put themselves beyond the possibility of defeat. Then they waited for an opportunity to defeat the enemy.”
This study was supported in part by the American Diabetes Association (grant 1-16-PDF-108). Work in the Perrimon lab is supported by the National Institutes of Health (grants R01AR057352 and P01CA120964). Perrimon is also an Investigator of the Howard Hughes Medical Institute.
Additional study authors are affiliated with Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Koç University in Turkey and Capital Medical University in China.