Taking the blinders off

The search for better drugs

Editor’s Note:  This story, originally published in 2005, has been updated.

Bill Snyder
Published: July, 2005

Illustration by Antonello Silverini
The withdrawal of the blockbuster painkillers Vioxx and Bextra from the market in 2004 and 2005 underscored an urgent need to upgrade the tools and science of drug discovery, say academic and government scientists.

“We are truly a blind man and the elephant,” says Christopher Austin, M.D., of the National Human Genome Research Institute.

The human genome may encode a million distinct protein targets, yet only about 500 of them have been “hit” by small-molecule drugs. Scientists are only beginning to understand how drugs aimed at a single target may affect diverse physiological pathways and systems.

“If you pull one lever, it’s going to have an effect on another lever, which is connected to two other levers,” Austin says. “Before you know it, you’ve pulled the tail of the elephant and you’ve made the elephant’s brain mad, and the elephant is going to pick up his foot—which you don’t know exists—and stomp on you ...

“You can see the leg coming up in the air, but you say, ‘Is that really a leg coming up in the air? I didn’t know that was there.’ You don’t know until it lands on you,” he says.

That’s what happened with the selective COX-2 inhibitors Vioxx and Bextra, Austin says.

The drugs were developed to relieve arthritis pain and inflammation without the gastrointestinal side effects of traditional anti-inflammatory drugs, which block both cyclooxygenase (COX) enzymes. Only after millions of people had taken the drugs for years did it become apparent that they increased the risk of heart attack and stroke.

“What we still really lack in the whole drug discovery/drug development pipeline is good enough predictive toxicology,” says Daniel Liebler, Ph.D., director of the Vanderbilt Proteomics Laboratory.

“We can certainly give a very toxic drug to a rat or a mouse or a dog, and observe classic signs of toxicity (such as) changes in liver and kidney function tests,” Liebler says. “But what we lack are good biomarkers for more subtle dysfunctions that will ultimately manifest themselves after the person’s taken the drug for six months… like with Vioxx.”

Proteomics, the study of proteins, is one avenue toward that goal.

In the last few years, through such technologies as mass spectrometry, scientists have identified protein markers that seem to correlate with the emergence or progression of certain diseases, and with the response of disease to treatment.

In a mouse model of breast cancer, for example, Vanderbilt researchers have shown that the level of several proteins plummeted within 12 hours after administration of Tarceva, a cancer drug that blocks the receptor for epidermal growth factor. This suggests that the proteins may be “biomarkers” for tumor growth.

“You could see these changes… way before any surgical or MRI (magnetic resonance images) will show you there is tumor shrinkage,” says Richard Caprioli, Ph.D., director of the Mass Spectrometry Research Center, who participated in the research.

More study is needed to determine whether a drop in the concentration of these proteins can be reliably correlated with tumor shrinkage in response to Tarceva. With the help of proteomics in the future, however, “we might be able to predict if a drug is going to be effective in a patient—even after the first dose,” Caprioli says.

Watching drugs work

Imaging technologies offer another avenue for predicting the effectiveness of drug therapy.

Researchers in the Vanderbilt University Institute of Imaging Science are exploring dynamic contrast imaging, an MRI method that can create a three-dimensional image of angiogenesis, new blood vessel formation. When standardized, this method may provide a way to determine the effectiveness of anti-angiogenic agents, says institute director John Gore, Ph.D.

Vanderbilt recently installed a 7 Tesla magnet, 140,000 times the strength of the Earth’s magnetic field, which will allow institute researchers to conduct magnetic resonance spectroscopy.

Using this technique, researchers can measure very precisely the levels of neurotransmitters in the brain. “We think that’s an important area,” Gore says, “not only for certain brain disorders such as addiction, but also for looking at the effects of drugs.”

Positron emission tomography or PET is another imaging technology that is being harnessed for drug discovery. By tacking a radioisotope of fluoride or carbon onto a drug, for example, researchers can use PET to detect the radiation emitted by the labeled drug, and create an image of where it goes in the body.

Fluorescence imaging techniques, such as two-photon excitation microscopy, potentially provide a way to look into the living cell and watch what happens when a drug hits its target. This not only may aid drug discovery; it may salvage a promising class of cancer drugs called MMP inhibitors that were largely abandoned by drug companies after several clinical trials failed to show any survival benefit in patients with advanced disease.

MMP stands for matrix metalloproteinases, enzymes that are thought to contribute to metastasis, the major cause of cancer deaths, by helping to increase the tumor’s blood supply and means of escape to other parts of the body.

Vanderbilt cancer researchers have developed a “proteolytic beacon” that can detect and measure MMP activity. The beacon is a fluorescent probe that releases a flash of fluorescence when split by the enzyme.

When an MMP inhibitor is given to block the enzyme, the beacon doesn’t flash as brightly. In this way, the researchers hope to determine the dose of drug necessary to inhibit these enzymes, as well as which patients are most likely to respond to therapy.

“What we found was a genetic polymorphism which is much more common in African-Americans than in Caucasians … This was a completely unexpected finding … When you propose these genetic studies, people will say, ‘Well, you’re going on a fishing expedition.’ And I say, ‘Yeah, but this time we caught a whale.’” David W. Haas, M.D., principal investigator, AIDS Clinical Trials Unit at Vanderbilt
Photo by Anne Rayner
“We’re talking about cellular-based screening, high-content screening,” says David W. Piston, Ph.D., professor of Molecular Physiology and Biophysics who is participating in the research. “If you’re doing front-line screening in the cell, you’re two steps closer to the patient.”

Eventually, data from these studies will be integrated with data from genomic and proteomic studies to build “3-D models” that more accurately predict drug activity. “You’re going to find a lot fewer things that take you down the wrong path,” Piston predicts.

Sidelining the side effects

One of the biggest barriers to the successful launch of a drug is the adverse drug effect or unexpected side effect that may not become apparent until late in clinical testing or after marketing.

While the adverse effect may occur in only a tiny minority of patients, it may be serious enough that the drug company has no choice but to flush the entire effort—perhaps 12 years of work and up to a billion-dollar investment—down the drain.

Advances in genetic research may come to the rescue. In the late 1970s and early 1980s, Vanderbilt scientists led by the late Grant Wilkinson, Ph.D., D.Sc., identified some of the first polymorphisms, or genetic variations, in a group of liver enzymes called cytochrome P450s that metabolize or break down drugs in the body. Drugs are more likely to reach toxic levels in people whose enzymes do a poor job breaking them down.

Wilkinson and his colleagues, including Richard Kim, M.D., and David Haas, M.D., also discovered that a polymorphism in a drug-metabolizing enzyme gene impairs the ability to metabolize the AIDS drug efavirenz. This polymorphism is about six times more common in African-Americans than in Caucasians, which may explain why efavirenz blood levels are generally higher in African-Americans.

Individuals with this genetic variant tend to accumulate higher levels of the drug in their blood, and as a result they may experience mental confusion, strange dreams and other central nervous system disturbances, says Haas, director of the Vanderbilt AIDS Clinical Trials Center. The side effects can be so disturbing that patients stop taking their medication.

Pharmacogenomics—the study of how genetic differences affect drug response—may lead to more “rational” drug development and prescribing. “It may be possible in the not-to-distant future to screen a person’s genome for polymorphisms that have clinical implications and then choose an appropriate regimen or an appropriate drug dose based on knowing their genetic background,” Haas says.

Haas says the polymorphism that affects the metabolism of the AIDS drug could not have been discovered without the help of a national DNA “repository” established by the Adult AIDS Clinical Trials Group, a federally funded group of 34 centers in the United States, including Vanderbilt, which evaluates new AIDS treatments.

In 2000, Haas and his colleagues began developing a process for obtaining informed consent to collect an extra blood sample for DNA studies from patients participating in AIDS clinical trials. Since then, the repository, which is housed at Vanderbilt, has collected about 8,000 samples from different individuals.

As of 2005, about 10 genetic studies had been undertaken using the DNA samples. Information from these studies is being used to help develop a vaccine against the AIDS-causing human immunodeficiency virus (HIV), and to develop treatments that can rebuild or “reconstitute” the immune systems of patients that have been damaged by HIV infection.

“It’s really just a glorious explosion of discovery,” Haas says.

DNA on deposit

Vanderbilt also has joined forces with the U.S. Food and Drug Administration, the pharmaceutical giant GlaxoSmithKline and First Genetic Trust, a Chicago-based company that has pioneered DNA banking, to advance genetic-based medicines and diagnostics.

The goal: to expand the collection of DNA samples from patients who suffer a rare adverse drug event called long QT syndrome. The syndrome can lead to potentially fatal arrhythmias, abnormal heart rhythms.

When physicians anywhere in the country report drug-induced long QT syndrome to the FDA, the agency will refer them and their patients to Vanderbilt for participation in the study.

“We’ve been interested in this rare adverse drug effect for many years, with the idea that it is genetically determined,” says Dan Roden, M.D., director of the John A. Oates Institute for Experimental Therapeutics at Vanderbilt and a principal investigator in the collaboration.

“The key first step in searching for genetic variants that may increase susceptibility is finding enough patients who have suffered this unusual event,” Roden says. If genetic variants are found, it may be possible to develop diagnostic tests that can be used to identify in advance people at high risk for this side effect if they take certain drugs.

“What the human genome is teaching us is that there is tremendous variability among individuals at the genetic level … and that it ought to be possible to understand how that variability … in a whole set of genes might perturb responses in an individual or in a group of people to drugs.” —Dan M. Roden, M.D., director of the John A. Oates Institute for Experimental Therapeutics at Vanderbilt
Photo by Anne Rayner
Genetic testing is not an easy sell, however. “There are drugs for which there are potentially very effective genetic tests that can predict, with a high degree of probability, side effects,” Haas says. “But the companies that make those drugs are not pushing for genetic testing because they think… they will lose market share.

“Suppose there are three drugs for providers to choose from, and one of them shows that a genetic test will help you prescribe it better,” he explains. “Most clinicians right now would rather just write the prescription for the other drugs and avoid genetic testing.

“Genetics is not going to be used to guide prescribing just because it makes sense. It will only happen if accomplished, forward thinking investigators, in partnership with the community, really push this forward and make it a reality.”

William Evans, Pharm.D., director and chief executive officer of St. Jude Children’s Research Hospital in Memphis, agrees. Evans and his colleagues pioneered the use of genetic testing to improve treatment of childhood cancers.

“The burden is on us at academic medical centers to begin to not only provide… evidence that these genetic polymorphisms are influencing significantly the drug response,” Evans said during a lecture at Vanderbilt, “but to begin to incorporate that into treatment plans and protocols and to show… that it actually makes a difference.”

Leigh MacMillan contributed to this story.

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