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Stephen Fesik, Ph.D.:
“My interest is to develop therapies that will have a dramatic effect on cancer patients. 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.”

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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. 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.

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.

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.


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