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【Cancer research】癌症图谱，如何解读？
After struggling for years to improve the treatment of cancer, scientists now hope to fight the disease with the help of the same techniques that deciphered the human genome eight years ago: mapping it.
Traditionally, researchers have started with a fuzzy premise about which toxic drugs might kill tumors and then tested those drugs in the lab, in animals and, finally, in human subjects. This helps explain why some 35 years after Richard Nixon declared a "war on cancer," there has been only limited progress in the treatment of most of the 200 cancers that afflict humans. In most cases, "we extend life a little at great cost," says geneticist Garth Anderson of the Roswell Park Cancer Institute in Buffalo, N.Y.
Now, scientists are trying to eliminate the guesswork by using powerful gene-sequencing machines to identify which genetic alterations cause which cancers -- an ambition reflected in three papers published this week. The hope is to offer differentiated treatment to patients based on their different tumor profiles. But the picture is enormously complicated. For example, scientists had expected to identify certain key genes that were frequently mutated. They found the opposite: a large number of mutated genes, but each mutated in a smaller fraction of the tumors.
"We used to think there was one enemy that was well-defined, but now we know there are lots of little enemies," says Victor Velculescu of Johns Hopkins Kimmel Cancer Center and a co-author of two papers in the journal Science. Stephen Eldridge, a professor of genetics at Harvard Medical School who wasn't involved with the recent studies but is familiar with the findings, says new knowledge of cancer's complexity suggests that it still won't be easy to find good treatments. But "it's a new era in cancer research," he says.
In the papers that came out this week, researchers provide a detailed blueprint of tiny genetic mutations that appear to be linked to two of the most lethal cancers: pancreatic cancer and a brain cancer known as glioblastoma multiforme. The findings suggest that cancer's molecular machinery appears to be far more intricate than anyone imagined.
Two separate papers in Science on pancreatic and brain cancer are the result of a private cancer-genome project led by researchers at Johns Hopkins. A third study, in Nature, also on glioblastoma, is the product of a far larger project funded by the U.S. National Institutes of Health.
After years of the hit-and-miss approach, targeted anticancer drugs such as Herceptin, for breast cancer, and Gleevec, for a type of leukemia, have arrived on the scene, sparking intense industry interest in agents that narrowly attack specific targets of a tumor's cellular machinery.
But the new research suggests that most brain and solid tumors are very different from these, says Bert Vogelstein, a co-author on the Science papers and a noted cancer researcher at Johns Hopkins. "It may be more productive to screen for specific pathways, which are a series of successive molecular changes in a cell. This is a very different perspective" from the approach currently taken by most drug companies, Dr. Vogelstein adds.
In their Science study, researchers said their genomic analysis of 24 samples of pancreatic cancers found an average of 63 genetic alterations, which in turn sit in 12 cellular pathways -- a more complex set of possibilities than previously believed. That might suggest that targeting the pathways could lead to new pancreatic-cancer treatments, researchers say. One downside: The pathways are also responsible for various key biological functions, so disrupting them could trigger severe side effects.
The Science study on glioblastoma, the type of brain cancer recently diagnosed in Sen. Edward Kennedy, looked at mutations in samples from 22 patients. The small study pinpointed a particular gene, IDH1, that has never been linked to cancer and found that patients with IDH1 mutations had a longer survival time -- suggesting a new treatment strategy.
However, George Miklos, an Australian geneticist who is skeptical about the clinical benefits of analyzing the mutations found in tumors, argues that such an analysis doesn't prove IDH1 variations are necessarily a direct cause of brain cancer. "If I were a pharmaceutical company, I'd be very leery about spending $500 million towards making a drug based on IDH1," he says.
Assembling a library of mutations for different tumors could also make it easier to quickly diagnose a tumor before it gets too large. Bits of DNA and even whole cells often dislodge from early-stage tumors and end up in the blood or other body fluids. That suggests tests based on mutations could spot the presence of a tumor before a patient shows symptoms -- leading to a quick excision of the cancer or earlier, more effective treatment.
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作者:admin@医学,生命科学 2010-10-22 22:06
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