'Playing Dirty' to Fight Cancer

[Guest guest]

Drug discovery:

Playing dirty

from Nature

Simon Frantz

Simon Frantz is news editor for Nature Reviews Drug Discovery.

Forget drugs carefully designed to hit one particular molecule — a

better way of treating complex diseases such as cancer may be to aim

for several targets at once, says Simon Frantz.

It's not often that a science lecture can turn a person on to the

idea of promiscuity. But when Heinrich heard a talk about a

promising new cancer drug, it triggered a transformation of his ideas

about how to target disease. It sounds heretical, but Heinrich and

others are now saying that 'magic bullet' drugs designed to hit

single biological targets might not be the answer to treating complex

illnesses such as cancer and cardiovascular disease. The future, they

say, could be in drugs that are less picky about their molecular

partners.

Heinrich's turning point was a seminar given in early 1998 at the

Oregon Health and Science University Cancer Institute in Portland,

where he worked. Druker, a molecular biologist in the medical

department at the same university, was talking about the

revolutionary leukaemia treatment Gleevec (imatinib mesylate). Made

by Swiss drug company Novartis, Gleevec was designed to zero in on a

single protein in cancerous cells, specifically killing them while

leaving healthy cells unharmed. It proved to be spectacularly

effective and non-toxic. Compared with the relatively indiscriminate

action and distressing side effects of conventional cancer

treatments, Gleevec seemed to vindicate the single-target approach to

drug discovery.

But it soon became clear that Gleevec was not as specific as its

creators had thought. The drug works by attaching to a key part of an

overactive protein that causes chronic myeloid leukaemia. In his

lecture, Druker revealed that the drug also inhibits a second

protein, known as the PDGF receptor. Sitting in the audience,

Heinrich had a brainwave. At the time, he was working on a protein

similar to PDGF called KIT. " We became interested in the idea that

Gleevec could probably inhibit KIT as well, " he says. Working with a

team led by Demetri and Fletcher at the Dana-Farber

Cancer Institute in Boston, Massachusetts, Heinrich found that

Gleevec was also remarkably effective against a rare cancer called

gastrointestinal stromal tumour, known to be linked to faulty KIT

activity1.

What Heinrich and his colleagues had stumbled on went the opposite

way from the direction that drug companies have been heading in since

the beginning of the 1980s. In a bid to take much of the guesswork

out of drug discovery, companies tried to avoid treatments that non-

selectively bound to several targets — what they term 'dirty'

or 'promiscuous' drugs — and focused on creating selective magic

bullets such as Gleevec. But researchers are now realizing that too

much specificity can also be problematic.

Take aim

Before the 1980s, drug discovery began by using animal models to test

compounds created by medicinal chemists. Drugs were deemed successful

by virtue of their effects rather than the number of molecular

targets to which they bound. For every safe and effective promiscuous

drug such as aspirin, there were good treatments that caused major

side effects, and plenty of other drugs that were just plain unsafe.

Trying to predict side effects and understand them was almost

impossible as in most cases no one knew exactly how the drugs worked.

The selective approach to drug discovery was made possible once

biochemical and genetic studies began to reveal the molecular

mechanisms that underlie common illnesses such as cancer and

cardiovascular disease. Companies were able to pick a protein that

they thought would make a good target, design compounds that interact

with this protein, and test these compounds to find potential drugs.

But 20 years down the line, it turns out that this target-based

approach doesn't always guarantee success. Some of these selective

drugs work in only a select population of patients. AstraZeneca's

Iressa (gefitinib), for example, is designed to treat lung cancer by

targeting a protein called EGFR. The drug does give an incredibly

potent response, but only in about one-tenth of the patients who

receive it2. And, as Gleevec fortuitously showed, treatments that

block more than one target can be tolerated better than previously

thought.

The idea that promiscuous drugs might be more effective than targeted

ones has also been emerging from efforts to understand how

antipsychotic drugs work. The schizophrenia drug Clozaril

(clozapine), for example, works because it targets a large number of

proteins, says Roth, a biochemist at Case Western Reserve

University in Cleveland in Ohio. Variations designed to bind to fewer

targets and reduce Clozaril's unpleasant side effects don't work as

well and still have similar side effects3.

In the 1990s, Roth and his team investigated which nerve-cell

receptors were being targeted by a range of antipsychotic drugs. They

found that the drugs that bound to the most receptors were the most

successful in the clinic. " What became clear to us when we examined

antipsychotic drugs was that the more targets they hit the better, "

says Roth.

Multiple choice

The reason for this is that common disorders such as cancer,

cardiovascular disease and depression tend to result from multiple

molecular abnormalities, not from a single defect. What's more,

pinpointing a single target is unlikely to help in many cases because

cells can often find ways to compensate for a protein whose activity

is affected by a drug, a phenomenon known as redundancy.

Using what Roth calls 'magic shotguns' to target multiple points in

these complex systems, could reap bigger therapeutic rewards than

fully blocking one target. " The idea of the magic bullet continues to

be a great idea, but in practice it's probably not going to be the

right approach for complex diseases, " says Roth.

Findings such as those of Heinrich, Roth and their colleagues have

triggered a recent shift in efforts to create drugs that hit more

than one target simultaneously. A number of companies and research

groups are now screening compounds that stick to several targets, or

are even trying to engineer promiscuous drugs. Arguably, the biggest

area for promiscuous drugs at the moment is cancer4.

A key set of targets includes enzymes called kinases. Many of these,

such as EGFR, influence how cells divide and are often abnormally

active in cancers. A slew of treatments (see ' " Dirty " drugs under

development', right) that block several kinases together are now in

clinical trials. The hope is that these will work better than highly

selective treatments, and that hitting more than one kinase at once

will reduce the chance of tumours becoming resistant to the drugs. In

August, Pfizer submitted a cancer drug called Sutent (sunitinib

malate), acquired when it bought the biotech company SUGEN, for

approval to the US Food and Drug Administration. The drug blocks not

only the proteins targeted by Gleevec, but also two other similar

molecules5.

Nevertheless, researchers in the field are frustrated that large drug

companies seem to be ignoring the advantages of promiscuity, or

polypharmacology as it is sometimes known. " There is still a

perception in the field that multi-kinase inhibitors are going to be

inherently toxic and non-selective and it's absolutely untrue, " says

Cherrington, executive vice-president for research and

development at Phenomix in San Diego, California, who helped develop

Sutent when she was at SUGEN. " I can remember having conversations

about this when we started to develop Sutent, and I'm still having

these conversations now. "

Big pharmaceutical companies are largely still wedded to the 'one-

target one-disease' model, and it's not easy to change this culture,

says Simon Mencher, principal at Natrogen Therapeutics in Milwaukee,

Wisconsin. " The first person I ever talked to in a large company

about promiscuous drugs said: 'I agree with you but I can't convince

the management to change the way they work' " he says. " Too much

funding has been sunk into targeting single agents. "

Sutent

Pfizer has submitted Sutent to the US Food and Drug Administration

(FDA) for approval as a therapy for kidney and gastrointestinal

cancer.

Sorafenib

Created by Bayer and Onyx Pharmaceuticals, this treatment for kidney

cancer is currently being considered by the FDA for approval.

Zactima

Made by AstraZeneca, Zactima is undergoing final (phase III) clinical

trials in lung cancer.

AG-013736

Designed by Pfizer, this drug is undergoing efficacy (phase II)

clinical trials for kidney and thyroid cancer.

Culture shock

Hopkins, head of knowledge discovery at Pfizer in Sandwich,

UK, agrees that the single-target approach remains the main strategy

in big companies. But this is now being challenged by fresh

information on some compounds, as well as by models mimicking the

effect of compounds on cells. In addition, large-scale genetic

projects have confirmed the extent of redundancy by showing that

altering the activity of many genes one at a time may have limited

clinical effect6. " Polypharmacology isn't new, what is new is the

realization of its importance in efficacy, " says Hopkins.

But screening for compounds that hit multiple targets is a difficult

task. Unlike the single-target strategy, in which the compound

selected is generally the one that sticks best to the target, the

most likely candidate for a multi-target drug will be one that

moderately influences several targets positively and negatively at

the appropriate concentrations.

Overcoming this problem requires a deeper understanding of the

cellular mechanisms at which the drug is aimed. To tackle this,

researchers have turned to the emerging field of network biology,

which can model the complex interactions between all the molecular

constituents of a cell7. By building these networks, researchers can

identify molecules and processes that are altered in diseases. They

can also predict whether it is better to design drugs that hit

multiple points in one process or that dampen parallel processes, and

whether redundancy will be a factor.

If multiple-kinase inhibitors prove successful in the clinic, they

could drive more efforts towards promiscuous drugs. Already the

Gleevec story is having an impact in industry, says Roth. He has

noticed a subtle change in the drugs that large companies are

licensing from smaller companies. " Both Pfizer and Merck have

licensed relatively non-selective antipsychotic compounds, " says

Roth. " The fact that they are doing this shows that they're getting

the message. "

References

Joensuu, H. et al. N. Engl. J. Med. 344, 1052–1056 (2001).

Cohen, M. H. et al. Clin. Cancer Res. 10, 1212–1218 (2004).

Roth, B. L., Sheffler, D. J. & Kroeze, W. K. Nature Rev. Drug Discov.

3, 353–359 (2004).

Mencher, S. K. & Wang, L. G. BMC Clin. Pharmacol. 5, 3 (2005).

Mendel, D. B. et al. Clin. Cancer Res. 9, 327–337 (2003).

Zambrowicz, B. P. & Sands, A. T. Nature Rev. Drug Discov. 2, 38–51

(2003).

Barabási, A. -L. & Oltvai, Z. N. Nature Rev. Genet. 5, 101–113

(2004).

relateds

© 2005 Nature Publishing Group