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New studies could lead to a treatment for cachexia

In 2011, Laura Beaver did not let the growing tumor in her body dictate her life. She kept up her normal hourlong gym routine. She took weekend bike rides near her Washington state home. She did the laundry, effortlessly walking up and down her spiral staircase, even though her breast cancer had returned.

Three-and-a-half years later, in February, her cancer had spread to her liver and bones. Beaver, 67, began chemotherapy again, eight years after doctors told her she was cured.

This latest round of chemotherapy was brutal. Beaver was constantly fatigued. Everything, even water, tasted like metal. But she learned to accept all the complications, until one day last month her exercise spandex fell off her protruding hips. She had been so preoccupied with chemotherapy that she never thought to step on the scale.


Her 5-foot-7, formerly 130-pound frame had shrunk to 116 pounds.

"My sternum looks like I've swallowed a huge German sausage," said Beaver, her voice coarse from the chemotherapy. "Now, I look like a skeleton."

Beaver's weight loss is symptomatic of cachexia, a condition that affects more than half of all cancer patients and kills at least 20 percent even before the cancer does. The cancer feeds off the muscles and protein in a patient's body, sapping her energy and causing her to literally waste away.

The extreme thinness is not caused by the cancer itself, but cachexia is most often a sign that a chronic disease — whether it's cancer, HIV/AIDS, tuberculosis, or kidney failure — is terminal. Little is understood about the syndrome, which often leaves patients too weak to receive further treatment for their chronic disease and greatly reduces their quality of life. The ability to reverse cachexia's effects has eluded doctors, who cannot treat the illness.

But two research papers published this month, in the journals Nature and Cell Metabolism, identify possible molecular causes of the degenerative illness that researchers hope could lead to potential treatments.


The Nature study, led by Dr. Bruce Spiegelman, a professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute , found that after using an antibody to block the effects of the protein PTHrP in mice with lung tumors, symptoms of cachexia improved or were prevented. PTHrP, or parathyroid hormone-related protein, is released from many types of cancer cells.

Cachexia causes white fat cells in the body that store calories to turn into fat-burning brown cells that release heat. Spiegelman found that the protein was at least partially responsible for this "browning" of the cells in mice, and identified high levels of PTHrP in blood samples from human cancer patients.

Although the protein does not cause cachexia alone, blocking the protein's release stopped the wasting, leaving Spiegelman and other doctors optimistic that this study could lead to a treatment to slow or prevent cachexia's effects.

"If we can improve treatment of that [cachexia], we leave people open for a longer time to get advanced therapies," Spiegelman said. "We want to know: What the heck is going on?"

The Cell Metabolism paper, detailing a different approach and led by Erwin Wagner of the Spanish National Research Centre in Madrid, states that inflammation plays a large role in turning white fat cells into brown fat cells, and found that anti-inflammatory therapies in mice alleviated symptoms of cachexia.


These studies are not the first aiming to understand cachexia's causes, but other attempted therapies and drugs have thus far been unsuccessful. While doctors are optimistic that this month's studies could improve cachexia treatment, the intracellular mechanisms that cause the wasting are poorly understood, said Dr. Alfred L. Goldberg, a professor of cell biology at Harvard Medical School who has studied cachexia extensively.

Cachexia research over the past several decades has focused on signaling pathways, the molecules that cells release to trigger functions in the body. But Goldberg said there are likely to be processes inside the cell that cause white calorie-storing cells to turn into brown fat-burning cells that have not been discovered. Understanding these mechanisms will be critical in developing an effective treatment, he added.

"All of these treatments are getting at the signals and not the intracelluar pathways because protein breakdown is very complex. We don't understand it well enough at that level," Goldberg said. "It's a challenging, variable problem . . . and it's hard to dissect."

But Dana-Farber's chief scientific officer Dr. Barrett J. Rollins , who has treated cancer cachexia patients, said the Nature study was one of the most promising because researchers were able to reverse cachexia in mice.

Although the cancer is often too advanced to treat, alleviating cachexia symptoms could improve a patient's quality of life, doctors said, either by enabling them to receive additional treatment to prolong their lives or reduce suffering.

"Patients with cachexia are miserable. They're weak, they're listless, they can't take care of themselves," Rollins said. "It's a terrible emotional problem to their loved ones — they're watching their loved ones melt right before their eyes."


If doctors can stop or at least slow the weight loss, they said, then a diagnosis of cachexia would no longer mean a hastened death.

Dr. Don S. Dizon, a gynecologic oncologist at Massachusetts General Hospital Cancer Center, said patients and their families often visit his office looking for a reason to remain hopeful — maybe their cancer can be cured, maybe the doctor can stop the weight loss so they don't look so sick. The extreme weight loss of cachexia, he said, visibly identifies the patients as terminally ill.

"It's very jarring for folks in their community to see someone they used to know look so different," Dizon said. "If we can get rid of this stigma by reversing cachexia, it'd mean a great deal to the patients."

Once Dizon tells his late-stage cancer patients that they are cachexic, patients' hopes shift — to hope that their suffering will be bearable, or that they can enjoy the time they have left with loved ones.

"It affects all aspects of their lives if they can't be the person they were before," said Dr. Janet Abrahm, a palliative care specialist at Dana-Farber and Brigham and Women's Hospital. "They're just too exhausted because they're too weak."

Beaver is still in treatment, but she no longer goes to the gym. Even climbing the stairs has become a Herculean task.


She's adjusted to her new weekly routine, which revolves around her chemotherapy schedule. Being driven by her husband four hours to Seattle for a day of chemotherapy. The next, drive back home across the state. Spend two days fatigued. One day rebuilding. Repeat.

Beaver has learned to live with the cancer, which she has battled for 13 years now. It's the weight loss that has depleted her.

"I have to take the stairs like a baby, one foot at a time," she said. "And I think, what happened to you?"

Yasmeen Abutaleb can be reached at yasmeen.abutaleb@globe.com. Follow her on Twitter @yabutaleb7.