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More on the Menu: Expanding the Selection of Cancer Therapies

December 2, 2009

By Melissa Marino

With the promise of personalized cancer medicine comes an unsettling question:

Even if we know the genetic profile of a patient’s tumor, do we have the corresponding therapies to treat it effectively?

Right now, probably not.pills

The online “Catalogue of Somatic Mutations in Cancer” lists more than 80,000 mutations in more than 13,000 genes that have been linked to cancer.

Currently there are only a few dozen targeted cancer therapies approved and in clinical use – many of them targeting the same biological pathway. And of the hundreds undergoing clinical trials, only one or two new drugs are approved each year.

That leaves a wide array of cancer-associated mutations without corresponding targeted therapies – and a lot of patients without the benefit of tailored treatment options.

“Recent advances in identifying the molecular drivers of some cancers allows us to more precisely predict who will benefit or not benefit from certain treatments,” says Jennifer Pietenpol, Ph.D., director of the Vanderbilt-Ingram Cancer Center. “But now, we need to understand those drivers for each and every tumor and have a wide menu of options to choose from so that each patient can benefit from this kind of precision.”

Drug discovery and development was once the exclusive realm of the pharmaceutical industry. And industry is certainly still critical in expanding the selection of new targeted cancer therapies. But academic institutions are becoming increasingly important in the discovery and development of drug candidates.

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,” says Larry Marnett, Ph.D., director of the Vanderbilt Institute of Chemical Biology, which is focused on applying chemical approaches to biological problems – such as drug discovery.

Researchers at Vanderbilt-Ingram and across the Vanderbilt campus are taking that next step to fill the menu with new drugs to offer those choices – for patients and their physicians.

No “one size fits all” for cancer
Drug discovery in oncology is plagued by one obstacle that most other diseases are not – the fact that cancer is not one disease but many.

“If someone says, ‘I have cancer,’ that’s almost like saying ‘I’m sick.’ It’s not defining the disease,” says Stephen Fesik, Ph.D., professor of Biochemistry and Pharmacology.

Cancers are driven by a host of genomic and cellular alterations – simple mutations, and chromosome rearrangements, amplifications and deletions, resulting in changes on the protein level. Even if two people have the same “tissue” type of cancer (for example, breast cancer), there may be different genetic factors driving their tumors.

“One person’s breast cancer can be very different from another person’s breast cancer, caused by very different mutations and genetic alterations. And while one patient may respond to one therapy, another breast cancer patient may not,” Fesik says.

“That makes it very difficult to treat because (the cancers) are not the same. It’s not the same target, not the same problem.”

And even within an individual’s tumor, one tumor cell may harbor vastly different mutations than its (also malignant) next-door neighbors.

“Heterogeneity is THE challenge with cancer versus other diseases,” Fesik says.

The mind-boggling complexities of cancer biology make it difficult to find treatments that are effective for all – or even most – patients.

“You might look at all that and say ‘This is impossible. How are you going to target it if all the targets are different, they vary between and within different patients…and over time, as resistance pops up?’ It seems impossible.”

Drugging the undruggable targets
Ready to take on this challenge, Fesik left Abbott Laboratories this year to come to Vanderbilt to lead the cancer drug discovery initiatives of the Vanderbilt-Ingram Cancer Center and the Vanderbilt Institute of Chemical Biology and Center for Structural Biology. As Abbott’s divisional vice president of cancer research from 2000 until his departure, he was responsible for building a pipeline of drug candidates with promising anti-cancer activity.

Stephen Fesik, Ph.D.

Stephen Fesik, Ph.D.

He knows the industry – and he knows drugs.

He also knows that industry alone can’t make the advances in cancer therapy that the half-million Americans who die each year of the disease need.

“Industry is looking more and more on the outside for their innovative drug molecules,” he says.

Using a technique he pioneered while at Abbott Laboratories – fragment-based drug design – he believes he can help fill up the therapeutic menu with candidate compounds that could make enormous strides against cancer.

“If we really want to see a change in how we treat cancer patients, we need to take risks. We need to go after these extremely difficult, challenging targets – but targets that make sense based on cancer biology,” Fesik says.

He’s not interested in making incremental improvements to existing drugs. His sights are set much higher.

“My interest is to develop therapies that will have a dramatic effect on cancer patients,” he says. “Not simply trying to change a drug that is currently given twice a day to once a day, or to eliminate a slight side effect … I’m looking for the cures. Not the extension of one month or two months, but actual cures.”

As formidable as the problem is, Fesik’s strategy is relatively simple.

Even though there are many different genetic alterations that drive tumors, there are some common themes and pathways that all or most cancers rely on to survive. This includes processes like angiogenesis (the growth of new blood vessels) and cell survival mechanisms (which keep tumor cells alive when the body would normally cause them to self-destruct).

The goal, Fesik says, is to develop drugs that act on highly validated targets within these common pathways known to be critical in many different cancers.

So, once you have identified that a particular pathway is altered in a particular cancer, you can develop pathway specific inhibitors and have something with which to treat the cancer.

“And that will be the mainstay of cancer treatment,” he explains. “You might say ‘That seems like a simple idea. Why doesn’t everybody do that?’”

The main problem is that many of these targets are considered “undruggable” by traditional methods, says Fesik. “It is very difficult to find a small molecule that’s going to bind to these targets and affect their function.”

Putting together the pieces
Fesik believes he knows how to overcome the problem of the “undruggable” target – by building drugs one small piece at a time.

Drug building:Illustration by Dominic Doyle In fragment-based drug design, a library of drug “fragments” (top panel) are screened to find fragments that bind to “subpockets” on a target protein’s binding surface (middle panel).

To read about fragment-based drug design, click on image.

The traditional approach to drug design involves the screening of a library of relatively large (at least on the chemical scale), intact compounds against the desired protein target, which has cup-like “pockets” to which drugs bind and can interfere with their activity. Then chemists make similar compounds – analogs – to try to find a molecule that will fit best into the binding pocket and affect the protein’s activity.

But a key limitation in this strategy is the limited numbers of existing chemical compounds that can be tested. So Fesik is taking a slightly different path to the final drug molecule.

Instead of altering the large, intact lead molecule, Fesik’s approach – fragment-based design – is to screen for fragments or pieces of that ultimate molecule and link them together, like Tinkertoys.

Once a high-throughput screen identifies chemical fragments that bind to “subpockets” on the target protein’s binding surface, the 3-dimensional structure of the protein binding to the drug fragments is determined with NMR spectroscopy or X-ray crystallography.

The 3-dimensional structures provide a picture of how the fragments fit into the protein’s binding pocket – and how they might be linked together.

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.

Larry Marnett, Ph.D.

Larry Marnett, Ph.D.

“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