Mapping the cancer genome

[AlaskaDenise]

What You Need to Know About Mapping the Cancer Genome

Three new studies examine genes linked to brain and pancreatic tumors

By Katherine Hobson
Posted September 4, 2008

Two of the most feared cancer diagnoses are glioblastoma, the most aggressive kind of brain tumor, and pancreatic cancer. Both kill the average patient within months, not years, of diagnosis, so there's special interest in finding the Achilles' heel of those cancers.

Scientists are now reporting that they've gotten an up-close-and-personal look at the genetic mutations linked to those two cancers, which may—eventually—lead to better matching of appropriate treatments to individual patients, new diagnostic tests, and possibly even entirely new drugs.

Beyond the implications for those specific cancers, there's a great deal of interest in the way the two groups of researchers approached their work: Both analyzed huge quantities of genetic information from different tumor samples in an attempt to essentially catalog the many different permutations of cancer. You're going to hear more about this approach in the future; one group, the government-funded consortium known as the Cancer Genome Atlas (TCGA) Research Network, is hoping to map even more cancers in coming years. And other researchers in the public and private sectors also are focusing on the cancer genome. Here's what you need to know:

What is the cancer genome, anyway?

Cancer, by definition, is caused by genes going haywire—mutating in ways that are not part of the normal blueprint for the body's form and function. Even among tumors of a single type, those genes can go haywire in many different ways. So describing the entire cancer genome involves characterizing all the different abnormalities that are linked to each of the 50 major types of cancer. That daunting task would involve churning through 12,500 times as much information as scientists processed in their recently completed effort to map the entire human genome.

What's the Cancer Genome Atlas project?

TCGA, as it's called, is a government-funded consortium charged with chipping away at this task. Now in a three-year pilot, it is focusing on just a few forms of cancer, including glioblastoma. (It just published a study in the journal Nature. That was one of three reports on the subject that appeared this week.) If those efforts prove promising, the full project, costing a proposed $1.5 billion and lasting many years, could get the green light.

But technology has not yet made it practical to characterize every single gene in every tumor, so the TCGA's approach is to focus on the genes already known to be active in tumors. Those genes still contain about 100 times as much genetic material as was mapped in the human genome project.

Are other researchers doing the same thing?

Yes. A separate group published two papers in Science, one describing glioblastoma and the other characterizing pancreatic cancer. The two groups' aims are the same, but their approaches are slightly different. The TCGA team looked at more than 200 tumor samples but analyzed only genes already identified as active in cancer, says Steve Elledge, a geneticist at Harvard Medical School. The group publishing in Science, by contrast, looked at fewer samples but cast a broader net: It studied all the genes in those samples, not just the ones previously known to be associated with cancer.

And it linked a new gene to glioblastoma.

So when will new gene-based cancer treatments be on the market?

Not soon. This is all very preliminary. The unifying conclusion of the new research is that there are many different mutations in a given type of tumor. That will make it difficult to come up with drugs targeted at every mutation. "The conclusion has subtly shifted," says Jeff Boyd, chief scientific officer of the Fox Chase Cancer Center in Philadelphia, who wasn't part of either research group. Now, he says, researchers are more likely to take aim at molecular "pathways" in a cancer cell. A pathway, in this case, is a sequence of molecular events in a cell that lead to a single end result but that may be sparked by several different types of mutations.

Think of it this way: Multiple cars might be taking their own routes to a given garage, but they're all planning to end up in the same place. Instead of trying to stop each car on the road, you could put up one roadblock in front of the garage. That promising approach to stopping cancer is attracting a lot of research attention and dollars, but there are as yet no drugs on the market targeting pathways, says Boyd. It's possible, but it would take years.

If not new treatments, then what?

More immediately, this kind of genetic mapping is likely to help characterize patients' tumors. Perhaps one type, sparked by a particular mutation, is more likely to respond to one therapy than another. Knowing that could help doctors decide which drug is the best to use for each individual patient. Also possible are new diagnostic techniques for identifying cancer earlier, though those, too, are years down the line.

What's the downside of mapping the entire cancer genome?

Some scientists question if the proposed effort is worth its anticipated price tag. At the very least, they argue that other strategies, such as looking at genes in tumors that aren't mutated but are still required for the cancer's survival, should be pursued in parallel to a cancer genome mapping effort. That's Elledge's view of things (his research lies within that alternative approach). The genome work is "bearing some fruit," he says. "The question is whether this fruit is worth the price." Christopher Logothetis is chairman of the department of genitourinary medical oncology at M. D. Anderson Cancer Center in Houston and a member of the external scientific committee for the TCGA. He says the new study was a successful pilot. "It demonstrated we could get people together, drive down the cost, find tissue, and learn something." Now, he says, it's time to figure out how to characterize the cancer genome, given limited resources, and whether it's best done by the public sector, private sector, or both.

http://health.usnews.com/articles/h...about-mapping-the-cancer-genome.html?PageNr=2

 

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Re: Mapping the cancer genome

In Long-Awaited Maps of Cancer,
The Breakthrough Is the Problem

By GAUTAM NAIK
September 5, 2008; Page A10

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.

<TABLE class=imglftbdy cellSpacing=0 cellPadding=0 width=262 align=left border=0><TBODY><TR><TD>

</TD></TR><TR><TD class=medcrd>Corbis </TD></TR><TR><TD class=medcptcrd>Glioblastoma, the type of brain cancer diagnosed in Sen. Edward Kennedy, is less damaging to some patients with certain gene mutations.</TD></TR></TBODY></TABLE>
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.

The Nature study, based on more than 200 samples of glioblastoma, was done by the Cancer Genome Atlas Research Network, a collaborative effort funded by the NIH. Launched in 2006, the project is a $100 million, three-year pilot program focusing on ovarian, lung and brain cancer. The hope is to expand it to include mutations found in 50 common human cancers.

Unearthing the genetic complexities of cancer "is still a massive task," says Prof. Michael Stratton, head of the cancer-genome project at the U.K.'s Wellcome Trust Sanger Institute. "But the drive of the science is inexorable."

http://online.wsj.com/article/SB122058186705402585.html?mod=googlenews_wsj

 

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Re: Mapping the cancer genome

Gene trawl shows curing cancer harder than thought

WASHINGTON (Reuters) - Cancer experts who probed every gene in tumors from two of the hardest-to-treat cancers found that cancer is much more complicated than anyone thought -- and say they found why a cure is so unlikely after a tumor has spread.

But they also discovered a potential new way to treat a common and fatal form of brain cancer, and opened the door to finding cancer before it has spread, when it can still be cured surgically, they reported on Thursday in the journal Science.

"Cancer is very complex -- more complex than we had believed. It is not going to be easy to develop therapies," said Dr. Bert Vogelstein of Johns Hopkins University in Baltimore and the Howard Hughes Medical Institute.

"If you have 100 patients, you have 100 different diseases."

The findings suggest that popular new targeted therapies such as Novartis's Gleevec may not work broadly, because they affect only one mutated gene, while cancer is caused by dozens.

A better approach would be to find the pathways -- networks of genes -- that control a tumor's uncontrolled growth and spread, they told reporters in a telephone briefing.

The international team sequenced the more than 20,000 genes in cells from 24 patients with advanced pancreatic cancer and from 22 patients with glioblastoma multiforme.

The typical pancreatic tumor had 63 genetic mutations, while the average brain tumor had 60, they found.

The good news is they found just 12 pathways that were abnormal in most of the tumors. Some were in expected areas, such as the regulation of programmed cell suicide, or apoptosis, the process by which abnormal cells self-destruct.

COMMON PATHWAYS

"Often what appeared to be mutations in disparate genes turned out to be working in common pathways," said Dr. Kenneth Kinzler of Johns Hopkins, who worked on the study.

One surprising discovery was a new gene called IDH1 found in glioblastoma multiforme, the most common type of brain tumor and one that usually kills patients within a year, said Dr. Victor Velculescu, also of Hopkins.
Massachusetts Sen. Edward Kennedy, 76, was diagnosed in May with this type of brain tumor.

The patients with these mutations were younger and lived longer than the typical brain tumor patient.
"Glioblastoma multiformes used to be thought of as one disease. It is now clear they are two," Velculescu told the briefing.

Vogelstein said the findings suggest that pharmaceutical companies should change their approach to developing new cancer drugs. While Gleevec, a pill, transformed the treatment of a blood cancer called chronic myeloid leukemia, "our work suggests that most solid tumors are really nothing like CML," Vogelstein said.

"It is extremely unlikely that drugs which target a single gene like Gleevec will be active against a major fraction of solid tumors. Instead of screening for drugs against single proteins, our work suggests that it may be more productive to screen for drugs that act against core pathways," Vogelstein said.

The findings also suggest better ways to screen for cancers, Vogelstein said.

"Our group as well as others have found that you can detect mutations outside of cells, just floating in the plasma, in virtually all patients with advanced colorectal cancer and about two-thirds of those with relatively early tumors," he said.

"It will be possible soon to detect them in many other samples from patients, say in their blood, even when the tumors are early. Almost all tumors and even those of the brain and pancreas would be curable if they are caught early."

http://www.reuters.com/article/newsOne/idUSN0437308620080904?sp=true