The Long Shot

by Douglas Quenqua Published Winter 2011-12
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No more cures?

Even if Stockwell were to identify his elusive molecule tomorrow, an approved drug would likely be ten to fifteen years away. That’s how long it typically takes for a pharmaceutical company to turn a molecule into a safe and effective drug.

In the meantime, Stockwell is pursuing other, more modest ways of improving cancer treatment. He recently made a breakthrough: he synthesized a molecule that, although it doesn’t bind to mutant Ras directly, is effective at killing certain types of cancer cells that contain the protein.

“This isn’t quite the home run we’ve been hoping for, because the molecule doesn’t seem to work against all Ras cancers, but one day it could dramatically improve treatments for some cancer patients,” says Stockwell, who reports his discovery in a forthcoming issue of a major academic journal. “We’re hoping that a pharmaceutical company will develop it into an actual drug that can operate in the human body.”

Stockwell believes the implications of his research go well beyond cancer. In The Quest for the Cure, he argues that scientists’ timidity in studying proteins that they fear are undruggable has contributed to a slowdown in drug discovery that has hobbled the entire pharmaceutical industry: the number of new drugs approved by the FDA annually has halved since the mid-1990s. In his own lab, Stockwell is also trying to disarm proteins that lie at the root of neurological diseases such as Huntington’s.

“All of the 20,000 or so drug products that have ever been approved by the U.S. Food and Drug Administration interact with just two percent of the proteins found in human cells,” he writes in The Quest for the Cure. “This means the vast majority of proteins in our cells — many of which, in theory, can modulate disease processes — have never been targeted before with a drug.”

Many scientists, he says, have taken this as evidence that these harmful proteins yet to be penetrated by drugs cannot be stopped. Pharmaceutical companies have also succumbed to this viewpoint, he says, shifting their priorities away from the discovery of new drugs in favor of finding new applications for existing ones.

“Pharmaceutical companies face tough economic questions,” Stockwell says. “Should they spend their money going after proteins considered to be the most elusive? Or should they focus, perhaps, on fine-tuning their existing drugs in order to discover new clinical applications for them or to improve them just enough so that they can be marketed as new products?”

Pfizer chose to market sildenafil citrate, a heart medication, as Viagra when the company realized that it could be used to treat erectile dysfunction, he points out. And many drug companies have made incremental advances in cancer treatment by combining therapies in novel ways.

“The thousands of drugs that already exist represented the low-hanging fruit, because they work on proteins in our body that were the first ones scientists were able to decode,” Stockwell says. “The prospect of creating new drugs for the trickier proteins is exciting, but it’s also incredibly time-consuming, expensive, and risky. So pharmaceutical companies are choosing to spend a lot of their resources tweaking and repurposing drugs in order to squeeze as much profit out of them as possible.”

This has occurred at the same time that federal funding agencies have gradually shifted their support away from exploratory science endeavors and toward “translational research” that aims to turn proven scientific concepts into real-world tools. “Federal funding agencies really should be stepping in to fund the more basic research that drug companies are backing away from,” says G. Michael Purdy, the University’s executive vice president for research. “But we shouldn’t let the drug companies off the hook. They’re choosing short-term profits over their own long-term financial health and medical progress. That’s going to come back and bite them.”

Luckily, some federal funding for unconventional projects exists. This fall, the National Institutes of Health awarded Stockwell its new EUREKA grant, for scientists conducting “innovative research on novel hypotheses or difficult problems.” The $1 million grant will support Stockwell’s search for a molecule that could bind with the Ras protein. 

Stockwell hopes that if he’s successful, his work will inspire other scientists — and funding agencies — to reopen the books on similarly dismissed proteins.

“In the course of time, an increasing percentage of proteins will likely be considered druggable,” he writes in The Quest for the Cure. “The day may even come, far into the future, when all disease-modifying proteins have been targeted successfully with drugs. This will represent the final triumph of human ingenuity, as we reach the pinnacle of medicine — when the majority of possible cures will have been realized.”

It’s a grand description of a utopian future. Which is exactly the point, Stockwell says. 

“The book and the research are really about the question rather than the answer,” he says. “There’s no magic bullet that’s going to fix all of these proteins that cause disease, but we need to go after them a lot more aggressively.”

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