The future of cancer drug development may be targeting pathways rather than single genes and their products.

Two new and unprecedentedly detailed analyses of pancreatic and brain cancers found dozens of mutations, but only a few were present in any given tumor. That could explain why gene-targeting cancer drugs have been so hard to develop: Even if a drug is successful, it will only affect a fraction of all tumors.

However, these varied mutations appear to influence only a few cellular pathways – cause and effect cascades of enzymes and signals that go haywire in cancer cells. Some scientists say that chemicals capable of disrupting pathways, whether at a cancer-implicated gene or somewhere else altogether, are far more promising than the current generation of gene-targeting cancer drugs.

"Virtually all drug development over the past ten years has focused on targeted therapies directed against individual genes or gene products," said Bert Vogelstein, a Howard Hughes Medical Institute cancer researcher and co-author of the studies, both published today in Science. "It's going to be even more difficult than previously expected to derive real cures from such therapies."

Vogelstein pointed to Gleevec, a leukemia drug known generically as Imatinib, as an exception that proves the rule: It targets tyrosine genes, and is one of the few modern cancer drug success stories. Most potential drugs developed in the last decade have failed during clinical testing, and of those that have come to market, few have significant impacts on a disease that will kill more than 560,000

Americans this year.

"A simple reliance on dominant gene product mode of drug discovery will likely be fraught with disappointment," said Lynn Hlatky, director of the Center of Cancer Systems Biology at Tufts University. She was not involved in the studies.

But other researchers say that pathway-targeting drugs are more complicated than they seem. Jackson Laboratory cancer researcher Tom

Gridley agreed "you'll never be able to come up with enough drugs to target each individual component," but held out hope that high-profile genes could still be targeted.

Further complicating the situation, said Harvard Medical School oncologist Lynda Chin, there are many different ways to disrupt pathways – and these have different clinical value.

"Sometimes you hit a different point in the pathway, and that works for one patient but not another," said Chin, a co-author of a brain cancer analysis published today in Nature by the Cancer Genome

Atlas project. Though not as detailed as the Science analyses, the

Nature study looked at 200 pancreatic cancer tumors.

"What's needed is an understanding of critical nodes," said Chin, suggesting that focusing on pathways – while an advance on single-gene, single-outcome thinking – is insufficient. "What the genome efforts give us is a network, not even a pathway. Everything is going to be interconnected. And at the end of the day, we still need to figure out what the key nodes are to target, and whether this should be done with a targeted drug or a pathway drug."

Gridley added that pathways don't function in isolation: Disrupt one, and another is affected, with potentially catastrophic side effects.

"Detecting the tumor and removing it as early as possible may be the way to go, because it's difficult to find drugs of the requisite efficacy and specificity," he said.

Vogelstein echoed his point, noting that "the history of medical research shows that the best way to control diseases in the long term is by prevention, not therapy." Chin was sympathetic: The mutations identified in the papers will eventually help doctors in their search for early genetic traces of cancer.

"There's a huge importance in early diagnosis. But that's not an alternative to therapeutics, it's a parallel," said Chin. "We know that there are patients who get diagnosed early, and the cancer still recurs. They will still die from the cancer, even with early diagnosis.

And we need to treat them, too."

Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses* [Science]*

An Integrated Genomic Analysis of Human Glioblastoma Multiforme [Science]

Comprehensive genomic characterization defines human glioblastoma genes and core pathways [Nature]

Image: Above, the crystal structures of two cancer-linked genetic mutations; below, the various pathways implicated in pancreatic cancers; courtesy of Nature.

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