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Cutting Cancer's Engine

Renewed interest in research about metabolism, the process cells use to fuel their growth, could lead to new types of cancer treatments. By Stephen Ornes

Not every hypothesis in cancer research has the same staying power. Some emerge with fanfare and hype, only to fade when follow-up research fails to support a promising theory—or when an upstart steals the spotlight. But even when a promising idea gets pushed aside, it’s not always gone for good. The perfect object lesson: treating cancer by disabling its metabolism, an idea that flared and faded, and now, like a trick candle on a birthday cake, has reignited.

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The basic idea behind the approach isn’t complicated. Cancer cells need energy to grow and proliferate; they get this energy from glucose and other nutrients and oxygen in the bloodstream. Cut off those energy supplies—or disrupt the process that turns the nutrients into cancer fuel—and the tumor cells die.

The concept appears to be once again gaining steam. The American Association for Cancer Research (AACR) hosted two special conferences within the last four years on metabolism and cancer to bring scientists together to discuss their latest work and catalyze new research efforts. Major cancer centers are conducting research that is attracting millions of dollars for the development of new drugs that can disrupt the chemical pathways that cancer cells—but not healthy cells—use to gain energy. Scientists are employing new technologies and tools that can illuminate the key players in a cell’s metabolism, which have the potential to be targets for new drugs. And there are now a number of multimillion dollar drug companies, run by leading cancer researchers, devoted exclusively to metabolism-targeted therapies.

So far, most of this work has been in the lab, and none of the investigational drugs that have made it into clinical trials have proved successful. But the companies are racing to develop and test a new generation of treatments. Undoubtedly, interest in metabolism as a treatment target has never been higher—at least not since the 1920s, when the idea first took the cancer research community by storm.

The Warburg Effect
At that time, it was German biochemist Otto Warburg who led the charge. Warburg initially became known for his research into how the cells of living organisms get energy. Then, in work that would earn him the 1931 Nobel Prize in Medicine or Physiology, he identified and described the function of a key enzyme that makes it possible for a cell to convert biochemical nutrients into energy. Ultimately, though, his goal was to cure cancer, and Warburg believed that his research on cells and energy would provide a way. Convinced that cancer is primarily a metabolic disease that arises when a healthy cell’s ability to turn food into energy goes haywire, he hypothesized that understanding how this process worked could lead to the development of a treatment that could kill cancer cells without harming healthy ones.

Warburg’s scientific predecessors had shown that tumors fed on the sugar glucose. Warburg dug deeper into this area, and found that cancer cells could survive on glucose alone, or on oxygen alone—but if they went without both for a few hours, they died. Using his research as a starting point, scientists would go on to discover that unlike healthy cells, which get most of their energy from oxygen, cancer cells obtain only about half of their energy this way; the rest they get from glucose, which they burn through 20 to 50 times as fast as healthy cells do—even when oxygen is also readily available. This voracious appetite for glucose, which is now observed in most types of cancer, is still called the “Warburg Effect.”

Warburg’s work caught on, and for decades other researchers also began looking for ways to capitalize on a tumor’s appetite for glucose. “Warburg was arguably the most powerful scientist in his time,” says cell biologist Lewis Cantley, the director of the Cancer Center at Weill Cornell Medical College and NewYork-Presbyterian Hospital in New York City. “At the time of Warburg’s initial work, through the middle of the 20th century, the major focus on research on cancer was really metabolism.”

But it didn’t last: After World War II, interest in cancer cell metabolism waned as other ideas bloomed.

Genetic Theories Move Forward
In 1953, James Watson and Francis Crick elucidated the structure of DNA—an advance that opened up a new field of research on the molecular underpinnings of cancer. Subsequently, scientists throughout the world began the push to identify the genes and genetic mutations that might play a role in cancer’s growth or inhibition. This research has helped pinpoint molecular markers that may indicate an individual’s elevated risk for cancer; it has also laid the groundwork for the targeted therapies—drugs designed to treat people whose tumors show specific genetic profiles—that are being developed or are in use today.


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