March 28, 2005

Huge Genome Project Is Proposed to Fight Cancer

By ANDREW POLLACK

pening a new front in the battle against cancer, federal officials are planning to compile a complete catalog of the genetic abnormalities that characterize it.

The proposed Human Cancer Genome Project, as it is being called for now, would be greater in scale than the Human Genome Project, which mapped the human genetic blueprint. It would seek to determine the DNA sequence of thousands of tumor samples, looking for mutations that give rise to cancer or sustain it.

Proponents say a databank of all such mutations, which would be freely available to researchers, would provide invaluable clues for developing new ways to diagnose, treat and prevent cancer.

"Knowing the defects of the cancer cell points you to the Achilles' heel of tumors," said Dr. Eric S. Lander, director of the Broad Institute, a genetic research center in Cambridge, Mass., that is affiliated with Harvard and the Massachusetts Institute of Technology.

The project would cost roughly $1.35 billion over nine years, but where the money will come from is still uncertain. For now, the government is likely to start with some smaller pilot projects, officials said.

Some scientists are dubious about the cost and are concerned that a big science project could take money away from smaller ones run by individual scientists.

Dr. J. Craig Venter, who led a private project to determine the human DNA blueprint in competition with the Human Genome Project, said it would make more sense to look at specific families of genes known to be involved in cancer.

"Diverting a billion or two dollars from other areas of research when it's not clear what answer we'd get, there might be better ways to move cancer research forward," Dr. Venter said.

But Dr. Lander and other proponents say the time is right for such an effort because the Human Genome Project has provided the underlying human DNA sequence with which tumor cells can be compared. In addition, the cost of sequencing is dropping. And discoveries of individual cancer-related genes have already helped lead to new drug therapies.

The proposal, presented last month to an advisory committee to the National Cancer Institute, was drawn up by a group led by Dr. Lander and Dr. Leland H. Hartwell, a Nobel laureate who is president of the Fred Hutchinson Cancer Research Center in Seattle. Drafters included Dr. Harold Varmus, a Nobel laureate and a former director of the National Institutes of Health, and Dr. Bruce Stillman, president of the Cold Spring Harbor Laboratory on Long Island.

Dr. Varmus, president of the Memorial Sloan-Kettering Cancer Center in New York, said the project could "completely change how we approach cancer."

Leaders of two agencies within the National Institutes of Health that would likely take the lead in financing the project said they were eager to go ahead.

"We are committed to do the sequencing of the cancer genomes," Dr. Anna D. Barker, deputy director for advanced technologies and strategic partnerships at the National Cancer Institute, said in an interview. "What we're trying to do is accelerate progress against this disease."

Dr. Francis Collins, director of the National Human Genome Research Institute, said, "I can confidently tell you that something will happen here."

The federal officials and Dr. Lander acknowledged that finding money for the project would be difficult in a time of tight budgets. They said that new money would probably have to be appropriated by Congress and that the pharmaceutical industry might contribute because the information would be useful for drug development.

The project, which might end up with a different name, would determine the sequence of the DNA in at least 12,500 tumor samples, 250 samples from each of 50 major types of cancer. By comparing the order of the letters of the genetic code in the tumor samples with one another and with sequences in healthy tissue, it should be possible to pinpoint mutations responsible for cancer.

But the proposition is extremely daunting. In general, each tumor cell holds a full panoply of human DNA, a string of three billion letters of the genetic code. So determining the full sequence of all the tumors would be the equivalent of 12,500 human genome projects. At a cost of many millions of dollars for one genome, the full project would be out of the question for now.

So the cancer proposal for now is to sequence only the active genes in tumors, which make up 1 percent to 2 percent of the DNA, Dr. Lander said. Even that would require at least 100 times as much sequencing as the Human Genome Project.

The work would cost nearly $1 million per tumor sample today, or a total of about $12.5 billion, according to the committee's proposal. The estimated cost of $1.35 billion is based on an expectation that sequencing costs will decline to one-tenth of what they are now in the next few years.

The Human Genome Project, now all but complete, cost $3 billion, but only about $300 million was spent on the actual DNA sequencing, with the rest going to development of technology.

"The technology available today would not be up to the task of doing this entire project," said Dr. Lander, who was a leader of the Human Genome Project. But he added, "The cost of sequencing is dropping enough that this is no longer unthinkable."

Indeed, he and Dr. Collins said, the project would promote further improvements in sequencing and show that it is still a useful technology.

"Some people have assumed that the genome project was over and sequencing wasn't worth investing in," said Dr. Collins, whose institute financed most of the Human Genome Project.

The Broad Institute, Dr. Lander's group, is a major DNA sequencing center and would presumably be a candidate for contracts for the cancer genome project. Many of the other people on the committee that put together the proposal represent institutions that might also receive grants from it.

There have already been some notable successes in using information about mutations to fight cancer, which is really a class of diseases in which cells in the body grow out of control because of the accumulation of mutations. While some of these mutations are inherited, most occur after a person is born.

Most cases of chronic myelogenous leukemia, a blood cancer, are caused by a particular chromosomal defect that leads to production of an aberrant protein. The drug Gleevec, which is designed to block this protein, has had remarkable success against this disease. Scientists have since found other genetic mutations that confer resistance to Gleevec, and companies are now using such information to design drugs to overcome that resistance.

The lung cancer drug Iressa can be very effective, but only in about 10 percent of patients who use it. Last year, scientists discovered that the drug seemed to work best in people whose tumors have mutations in a particular gene.

Just in the last few days, researchers led by Dr. D. Gary Gilliland of Brigham and Women's Hospital in Boston and Harvard reported that three types of leukemia appear to be caused by mutations in the same gene.

There are already some smaller projects under way looking for mutations, either in a particular type of cancer or in particular types of genes.

The Wellcome Trust Sanger Institute in Britain, a major participant in the Human Genome Project, has had a cancer genome program for several years. It has discovered a particular mutation in about two-thirds of cases of melanoma, a deadly skin cancer.

Scientists at Johns Hopkins University have unraveled some genetic changes involved in the origin of colon cancer. They are now working with Perlegen Sciences, a genomics company in California, on a comprehensive genetic scan of colorectal tumors.

But backers of the cancer genome project say faster progress could be made with one big, coordinated effort. And they say that despite the progress so far, scientists understand only a minority of the genetic changes involved in cancer.

There are other potential obstacles besides the cost of sequencing. One would be distinguishing which mutations are important, because many of those found would have nothing to do with cancer. The proposal says researchers should focus on mutations that occur in at least 5 percent of tumors of a certain type.

Yet another problem is that tumors can mutate so rapidly that two cells in the same tumor may have different mutations. So some mutations may be missed, depending which cells are used for the genetic analysis. "We can spend $2 billion on something and get a lot of data, but I'm not convinced it will do us much good," said Dr. Garth Anderson, an expert on cancer genetics at the Roswell Park Cancer Institute in Buffalo.

And in some cases cancer is caused not by changes in the sequence of DNA but by so-called epigenetic changes, in which the attachment of a chemical to DNA turns off a gene.

"To concentrate only on mutations, you might pick up 50 percent of what you need to know or even less about what goes into the initiation and maintenance of cancer," said Dr. Stephen B. Baylin, a professor of oncology and medicine at Johns Hopkins.

The proposal for the project does mention looking for epigenetic changes, but says the technology to study them is not well developed.

Supporters of the project say that the barriers can be overcome and that the project should proceed.

"Whether it's practical, whether it's doable, how much it costs, I take that out of the picture," said Dr. Brian Druker, a professor at the Oregon Health and Science University who helped develop Gleevec and also served on the committee that drew up the proposal for the cancer genome project. "These are the starting blocks that we need to develop a cure."