Shattering the syndrome

When thinking about research at St. Jude Children’s Research Hospital, what words spring to mind?  Catastrophic diseases. Perhaps cancer. Certainly children.

Research at St. Jude encompasses all of those, but discoveries in those areas have also translated into diseases such as diabetes and Parkinson’s disease, which also affect adults. Results from a recent St. Jude study might one day shatter another disease—one that currently affects 10 percent of the population. This is a direct example of how St. Jude is furthering its mission of sharing knowledge around the globe.

Metabolic syndrome is a group of conditions—obesity, insulin resistance, high blood pressure, low levels of good cholesterol and high blood sugar levels—that occur together. These conditions can increase the risk of serious complications like type 2 diabetes, heart attack and stroke. Metabolic syndrome afflicts up to one in four adults in the United States, and its occurrence is increasing in developing countries like India and China where people are adopting Western lifestyles,  diets and behaviors.

Eating a balanced diet, exercising, maintaining a healthy weight and avoiding tobacco can reduce the risks associated with metabolic syndrome, but what if a treatment were available to help or even prevent the disorder? Researchers at St. Jude—in collaboration with scientists at Washington University School of Medicine in St. Louis, Missouri—have found that chloroquine, a drug commonly used to treat malaria, shows potential as a treatment for metabolic syndrome.

“Results like this are a very nice example of how research at St. Jude impacts other diseases and science that is conducted in other institutions,” says Michael Kastan, MD, PhD, St. Jude Cancer Center director.

Fragments of questions

The key to choloquine’s effectiveness against metabolic syndrome is a protein called ATM—known to researchers for its role in the cell’s response to stress and DNA repair. ATM has been studied at length by Kastan because of its link to cancer.

“In our lab we study how cells respond to stress, in particular DNA damage,” Kastan says. “DNA damage responses are important determinants of whether cancers start, of how tumors respond to therapy, and of the toxicities experienced by patients receiving cancer therapies. Thus, how cells respond to DNA damage is very important in several aspects of cancer biology.”

The researchers began this journey of discovery with studies of a rare, recessive genetic disorder called ataxia telangiectasia (A-T). A-T is a complex disorder in which children experience a progressive neurodegeneration and other abnormalities. The disease causes devastating damage to the part of the brain that controls muscle function and coordination; patients with A-T are also at high risk for developing certain cancers, immunological disorders and lung problems. Because of this correlation, St. Jude created the world’s only clinic specifically designed to treat children with A-T and cancer.

“Several years ago, we found that the ATM protein, made by the gene that is missing in A-T patients, plays a role in insulin signaling and how cells respond to insulin,” Kastan says. “The reason we looked at that is because we knew from our work with A-T patients that some of them tend to have a strange type of diabetes. So, we explored the reason for this. In looking at insulin signaling, we found that the ATM protein—which is an enzyme—can get activated by insulin in certain cell types.”

Also, parents of A-T patients had been reported to have a higher incidence than normal of cardiovascular disease. Kastan wondered: With the link between insulin and ATM—and the apparent increase in cardiovascular disease in the parents of A-T patients—would ATM play a role in insulin resistance and cardiovascular disease?

Because this type of research is not done at St. Jude, Kastan called a colleague to help.

“I partnered with a scientist at Washington University who is an expert in insulin signaling and cardiovascular disease,” Kastan says. “Dr. Clay Semenkovich was a medical school classmate of mine, and I consider him one of the world’s experts in this type of research. He was very interested in studying it.”

The big break

In 2000, the researchers began to explore a potential role for the A-T gene in metabolic syndrome. Would loss of ATM affect the symptoms of high cholesterol, high blood pressure, insulin resistance with type 2 diabetes, atherosclerosis, and fat build-up in the central part of the body, which are all part of metabolic syndrome? The answer was that missing just one copy of the ATM gene, which happens in up to 1 in 100 Americans, made metabolic syndrome much worse. Missing both copies, as occurs in A-T patients, is even worse.

In 2003, Kastan’s laboratory published a paper in the journal Nature about how ATM works and how it gets activated by DNA damage. The study described how a critical early step in a cell’s response to DNA damage, a chemical modification of ATM, allows the enzyme to initiate a series of events that ultimately halt the growth of a damaged cell and help the cell survive.

The finding was important because DNA damage caused by radiation and environmental toxins can lead to mutations or cell death and can also contribute to the development of cancers. At the same time, the researchers discovered that the drug chloroquine could activate the ATM enzyme in cells without causing DNA damage.

The St. Jude/Washington University team reasoned that if loss of ATM makes metabolic syndrome worse, then perhaps activating ATM would make it better. The researchers asked whether chloroquine could improve the symptoms of metabolic syndrome. They found that low doses of chloroquine could reduce blood pressure, decrease hardening and narrowing of the arteries, and improve blood sugar tolerance. The next step was to determine if chloroquine helps by activating ATM.

“Loss of ATM made symptoms of metabolic syndrome worse,” Kastan says. “We found that chloroquine made it better and did so by working through ATM.”

According to Kastan, medical literature already contains a great deal of information showing that humans can take chloroquine safely and generally tolerate the drug well.

“The results of our studies suggest that we may be able to provide people with these protective benefits using very low and perhaps infrequent doses of such a drug,” Kastan says. “The good news is that chloroquine is a proven drug. It’s used frequently for treating malaria as well as for certain autoimmune diseases. Here we have a drug that can impact a disease that affects 10 percent or more of the population.”

Smashing the side effects

Following these studies, a small pilot clinical trial of chloroquine use was initiated in adults with symptoms of metabolic syndrome at Washington University. The study is showing promising results.

“We just received funding for a new clinical trial, and we’re very excited to see if the processes activated by chloroquine can effectively treat one of the most common health problems of modern industrialized society,” says Clay Semenkovich, MD, professor of Medicine, Cell Biology and Physiology at Washington University. “We already know that chloroquine is safe and well-tolerated, and our results suggest we may only need very low and perhaps infrequent doses to achieve similar effects in humans.”

How do all of these studies relate back to catastrophic childhood diseases at St. Jude? Kastan’s colleagues in the St. Jude Epidemiology and Cancer Control department have found that survivors of childhood cancer have a high frequency of metabolic syndrome when they get older. The findings may lead to useful treatment options for these patients.

“The fact that our patient population has a significant problem with metabolic syndrome has been well documented in our After Completion of Therapy clinic,” Kastan says. “When they get older, children who were treated with chemotherapy and radiation therapy appear to have a much higher incidence of metabolic syndrome than the general population. So, this could have a significant impact on our survivor population—to be able to have a treatment that helps them avoid one of the long-term side effects of treatment.”

Putting the pieces together

St. Jude is continuing basic science studies in relation to ATM on the molecular level.

“The more we understand the basic science, the more we can discover and design drugs even better than chloroquine,” Kastan says.

According to Kastan, the ultimate goal is to have a chloroquine-type drug available for the large percentage of the population who may benefit from its protective effects. “Metabolic syndrome and obesity are becoming almost pandemic and are affecting people younger and younger,” he says.

Theoretically, use of choloquine or derivative drugs could also potentially help insulin-dependent diabetics because it might reduce their insulin requirements.

“This research shows how basic discoveries can impact clinical medicine, and it shows the importance of being able to do the clinical trials,” Kastan adds. “For a laboratory discovery to have this kind of potential clinical impact is the ultimate. What could be better than to make a discovery in your lab that has an impact on clinical disease, especially on prevention of disease? Prevention is the best treatment. It’s what we all work for. We will continue to strive for these types of impacts.”

Reprinted from Promise magazine, spring 2007

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