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Larry Marnett, Ph.D.:
Academic centers should not only generate basic discoveries about cancer biology, “but then take that next step toward trying to use that information in a fashion that will benefit patients.”

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The fragments can then be assembled into a larger molecule that better fills up the target protein’s binding pocket.

“It’s a modular approach to drug discovery. In principle, it’s like screening a much larger library of compounds,” explains Fesik. “And you’re tailoring the molecule for binding to the protein.”

This method, he says, “is a great way to create molecules that have never been made before and therefore would not have been found in a traditional high-throughput screen.”

And clinical trials are now bearing out the utility of this strategy. A drug candidate that targets a protein (called Bcl2) involved in programmed cell death (apoptosis) – which Fesik developed at Abbott using fragment-based drug design – is now entering Phase II clinical trials and showing promise against some lymphomas, leukemias and other cancer types.

“It’s a great strategy,” says Marnett. “The targets he is going after are ones that others have tried and failed. This is exactly the kind of thing we should be doing.”

Having an industry-like drug development capability – and the expertise of a leader in the field of drug discovery – will also help other Vanderbilt cancer researchers take their findings about drug targets a step beyond what had been previously available in academia.

Marnett’s lab, for example, has identified a molecule that helps cancer cells ward off toxic stressors like chemotherapy. Cancer cells tend to evolve ways to escape the body’s natural immune defenses that would otherwise kill them off. Marnett’s target is, interestingly, a chaperone protein that binds to the Bcl2
proteins that Fesik worked on previously at Abbott.

“We believe that by eliminating this chaperone – and we’re hoping to do that with drug-like molecules – that the cancer cells will become sensitive to compounds like the Bcl2 antagonist (drug developed at Abbott),” says Marnett, who also directs the A. B. Hancock Jr. laboratories, Vanderbilt’s first cancer research lab founded in 1972.

Industrious in academia
But why would researchers at an academic institution be able to accomplish what industry has not been able to?

Because, Fesik says, Vanderbilt has assembled the infrastructure – including strong centers in structural biology, chemical biology, imaging and proteomics – to go after these high-risk, undruggable targets.

“At Vanderbilt, I can carry these studies out and do things that might be against the ‘dogma’ about what’s doable and not doable. It’s a great environment to do high quality, innovative science and, in particular, cancer drug discovery,” he says.

“Even though (drugging these targets) might be technically challenging, if we get it, it will affect the lives of many patients.”

The hope is to, in time, establish a formal cancer drug discovery program similar to Vanderbilt’s Program in Drug Discovery in neuroscience. It may take time – and additional funding – to realize that dream.

But this is exactly what academia should be doing, says Marnett.

“In the area of drug discovery, (academia) should not try to replicate what’s going on in industry – because the resources are just so totally different – but we should be looking at projects that are very high risk and relatively low cost. We can take things up to a point, but it all comes down to resources.”

Marnett predicts that Vanderbilt’s cancer drug discovery efforts will show real results on fairly short order.

“I think we can definitely get drug candidates that work in animals. And once you’ve got something that works in an animal and have validated your target, that’s a pretty valuable package (for a drug company to then license and continue developing),” he says.

With Fesik’s focus on cancer drugs coupled with the existing research infrastructure at Vanderbilt, “we’ve now got all the tools in place,” says Marnett.

“We will test new therapeutic hypotheses, and we’ll definitely have molecules that will get as far as the clinic. I can’t promise they’re going to work in the clinic. But I’m very convinced that Vanderbilt has the strongest academic drug discovery program in the country.”

Fesik agrees that the potential exists to make important advances in cancer drug discovery. That’s why he chose to leave industry and come to Vanderbilt.

“What’s driving me the most is the dramatic effects we may be able to have on the lives of cancer patients,” Fesik says. “The only thing that can stop this is the lack of funding.”

“We want to do risky things. The reason the pharmaceutical industry is successful from a monetary viewpoint is that they don’t. They can still make money with less risk,” Fesik explains. “But we’re not a company. We have different goals. However, to succeed at reaching our goals we need additional funding from the outside.”

Tailor-made drugs on the menu
Fesik’s fragment-based drug design, which essentially “tailors” a drug compound to fit a target protein, goes hand-in-hand with the goal of personalized medicine, which “tailors” therapy to fit the particular genetic profile of an individual’s cancer.

For decades, surgery, chemotherapy and radiation have been the gold standard treatments for cancer. But they are essentially “one-size-fits-all” treatments.

One of the most important advances in recent years has been the development of targeted therapies – drugs designed to kill only cells with particular molecular malfunctions as opposed to the less discriminating assault of traditional chemotherapy and radiation (which tend to kill all rapidly dividing cells).

These targeted drugs – like Iressa, Tarceva and Erbitux – have certainly helped some cancer patients live longer, but most
targeted therapies only work in a small percentage of patients. And, when they do work, they seem to add only another few weeks to months of disease-free survival.

The disappointing results – again due to the fact that no two cancers are the same – highlight the importance of developing new anti-cancer drugs that will allow physicians more options in achieving truly personalized cancer care.

“Personalized medicine was a fantasy a few years ago because we didn’t have much targeted therapy,” Fesik says. “It didn’t much matter whether you could determine what is driving the tumor if you have nothing to offer the patient that takes advantage of that knowledge.”

Now that more and more targeted therapies are being developed – and hopefully several more that Fesik and colleagues will add to the list – personalized medicine seems within our reach.

“In the future, you could envision that you would diagnose the patient – not by tissue type but by the genetics – and then you would have this arsenal of weapons that you could use to treat the specific genetic malfunctions that are keeping the tumor alive,” he says. “These are exciting times in cancer research as we get one step further to effectively treat cancer patients with new, innovative therapies.” bullet

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For more information about the Vanderbilt Institute of Chemical Biology, see: www.vanderbilt.edu/vicb


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