Article about IM and molecular-targeting drugs/NYT

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December 27, 2005

Preventing Cancer

Slowly, Cancer Genes Tender Their Secrets

By GINA KOLATA

Jay Weinstein found out that he had chronic myelogenous leukemia in

1996, two weeks before his marriage.

He was a New York City firefighter, and he thought his health was great.

He learned that there was little hope for a cure. The one treatment

that could save him was a bone marrow transplant, but that required a

donor, and he did not have one. By 1999, his disease was nearing its

final, fatal phase. He might have just weeks to live.

Then, Mr. Weinstein had a stroke of luck. He managed to become one of

the last patients to enroll in a preliminary study at the Oregon

Health & Science University, testing an experimental drug.

Mr. Weinstein is alive today and still taking the drug, now on the

market as Gleevec. Its maker, Novartis, supplies it to him free

because he participated in the clinical trial.

Dr. Druker, a investigator at the university's

Cancer Institute, who led the Gleevec study, sees Mr. Weinstein as a

pioneer in a new frontier of science. His treatment was based not on

blasting cancer cells with harsh chemotherapy or radiation but instead

on using a sort of molecular razor to cut them out.

That, Dr. Druker and others say, is the first fruit of a new

understanding of cancer as a genetic disease. But if cancer is a

genetic disease, it is like no other in medicine.

With cancer, a person may inherit a predisposition that helps set the

process off, but it can take decades - even a lifetime - to accumulate

the additional mutations needed to establish a tumor. That is why,

scientists say, cancer usually strikes older people and requires an

element of bad luck.

" You have to get mutations in the wrong place at the wrong time, " Dr.

Druker says.

Other genetic diseases may involve one or two genetic changes. In

cancer, scores of genes are mutated or duplicated and huge chunks of

genetic material are rearranged. With cancer cells, said Dr.

Hahn, an assistant professor of medicine at Harvard Medical School,

" it looks like someone has thrown a bomb in the nucleus. "

In other genetic diseases, gene alterations disable cells. In cancer,

genetic changes give cells a sort of superpower.

At first, as scientists grew to appreciate the complexity of cancer

genetics, they despaired. " If there are 100 genetic abnormalities,

that's 100 things you need to fix to cure cancer, " said Dr. Todd

Golub, the director of the Cancer Program at the Broad Institute of

Harvard and M.I.T. in Cambridge, Mass., and an oncologist at the

Dana-Farber Cancer Institute in Boston. " That's a horrifying thought. "

Making matters more complicated, scientists discovered that the

genetic changes in one patient's tumor were different from those in

another patient with the same type of cancer. That led to new

questioning. Was every patient going to be a unique case? Would

researchers need to discover new drugs for every single patient?

" People said, 'It's hopelessly intractable and too complicated a

problem to ever figure out,' " Dr. Golub recalled.

But to their own amazement, scientists are now finding that untangling

the genetics of cancer is not impossible. In fact, they say, what

looked like an impenetrable shield protecting cancer cells turns out

to be flimsy. And those seemingly impervious cancer cells, Dr. Golub

said, " are very much poised to die. "

The story of genes and cancer, like most in science, involves many

discoveries over many years. But in a sense, it has its roots in the

1980's, with a bold decision by Dr. Bert Vogelstein of s Hopkins

University to piece together the molecular pathways that lead to cancer.

It was a time when the problem looked utterly complicated. Scientists

thought that cancer cells were so abnormal that they were, as Dr.

Vogelstein put it, " a total black box. "

But Dr. Vogelstein had an idea: what if he started with colon cancer,

which had some unusual features that made it more approachable?

Colon cancer progresses through recognizable phases. It changes from a

tiny polyp, or adenoma - a benign overgrowth of cells on the wall of

the colon - to a larger polyp, a pre-cancerous growth that, Dr.

Vogelstein said, looks " mean, " and then to a cancer that pushes

through the wall of the colon. The final stage is metastasis, when the

cancer travels through the body.

" This series of changes is thought to occur in most cancers, but there

aren't many cancers where you can get specimens that represent all

these stages, " Dr. Vogelstein said.

With colon cancer, pathologists could get tissue by removing polyps

and adenomas in colonoscopies and taking cancerous tumors in surgery.

Colon cancer was even more appealing for such a study because there

are families with strong inherited predispositions to develop the

disease, indicating that they have cancer genes that may be discovered.

So Dr. Vogelstein and his colleagues set out to search for genes " any

way we could, " Dr. Vogelstein said. Other labs found genes, too, and

by the mid-1990's, scientists had a rough outline of what was going on.

Although there were scores of mutations and widespread gene deletions

and rearrangements, it turned out that the crucial changes that turned

a colon cell cancerous involved just five pathways. There were dozens

of ways of disabling those pathways, but they were merely multiple

means to the same end.

People with inherited predispositions to colon cancer started out with

a gene mutation that put their cells on one of those pathways. A few

more random mutations and the cells could become cancerous.

The colon cancer story, Dr. Druker said, " is exactly the paradigm we

need for every single cancer at every single stage. "

But scientists were stymied. Where should they go from there? How did

what happens in colon cancer apply to other cancers? If they had to

repeat the colon cancer story every time, discovering genetic

alterations in each case, it would take decades to make any progress.

The turning point came only recently, with the advent of new

technology. Using microarrays, or gene chips - small slivers of glass

or nylon that can be coated with all known human genes - scientists

can now discover every gene that is active in a cancer cell and learn

what portions of the genes are amplified or deleted.

With another method, called RNA interference, investigators can turn

off any gene and see what happens to a cell. And new methods of DNA

sequencing make it feasible to start asking what changes have taken

place in what gene.

The National Cancer Institute and the National Human Genome Research

Institute recently announced a three-year pilot project to map genetic

aberrations in cancer cells.

The project, Dr. Druker said, is " the first step to identifying all

the Achilles' heels in cancers. "

Solving the problem of cancer will not be trivial, Dr. Golub said.

But, he added, " For the first time, we have the tools needed to attack

the problem, and if we as a research community come together to work

out the genetic basis of cancer, I think it will forever change how we

think about the disease. "

Already, the principles are in place, scientists say. What is left are

the specifics: the gene alterations that could be targets for drugs.

" We're close to being able to put our arms around the whole cancer

problem, " said Weinberg, a biology professor at the

Massachusetts Institute of Technology and a member of the Whitehead

Institute. " We've completed the list of all cancer cells needed to

create a malignancy, " Dr. Weinberg said. " And I wouldn't have said

that five years ago. "

The list includes roughly 10 pathways that cells use to become

cancerous and that involve a variety of crucial genetic alterations.

There are genetic changes that end up spurring cell growth and others

that result in the jettisoning of genes that normally slow growth.

There are changes that allow cells to keep dividing, immortalizing

them, and ones that allow cells to live on when they are deranged;

ordinarily, a deranged cell kills itself.

Still other changes let cancer cells recruit normal tissue to support

and to nourish them. And with some changes, Dr. Weinberg said, cancer

cells block the immune system from destroying them.

In metastasis, he added, when cancers spread, the cells activate genes

that normally are used only in embryo development, when cells migrate,

and in wound healing.

But so many genetic changes give rise to a question: how does a cell

acquire them?

In any cell division, there is a one-in-a-million chance that a

mutation will accidentally occur, Dr. Weinberg notes. The chance of

two mutations is one in a million million and the chance of three is

one in a million million million million.

This slow mutation rate results from the fact that healthy cells

quickly repair damage to their DNA.

" DNA repair stands as the dike between us and the inundation of

mutations, " Dr. Weinberg said.

But one of the first things a cell does when it starts down a road to

cancer is to disable repair mechanisms. In fact, BRCA1 and 2, the gene

mutations that predispose people to breast and ovarian cancer, as well

as some other inherited cancer genes, disable these repair systems.

Once the mutations start, there is " a kind of snowball effect, like a

chain reaction, " Dr. Vogelstein said.

With the first mutations, cells multiply, producing clusters of cells

with genetic changes. As some randomly acquire additional mutations,

they grow even more.

In the end, all those altered genes may end up being the downfall of

cancer cells, researchers say.

" Cancer cells have many Achilles' heels, " Dr. Golub says. " It may take

a couple of dozen mutations to cause a cancer, all of which are

required for the maintenance and survival of the cancer cell. "

Gleevec, researchers say, was the first test of this idea. The drug

knocks out a gene product, abl kinase, that is overly abundant in

chronic myelogenous leukemia. The first clinical trial, which began

seven years ago, seemed like a long shot.

" The idea that this would lead to therapy was something you wrote in

your grant application, " said Dr. Sawyers, a

investigator at the University of California, Los Angeles. " It wasn't

anything you believed would happen soon. "

But the clinical trial of Gleevec, conducted at the Oregon Health &

Science University, U.C.L.A. and M. D. Cancer Center in

Houston, was a spectacular success. Patients' cancer cells were beaten

back to such an extent that the old tests to look for them in bone

marrow were too insensitive, Dr. Sawyers said.

Gleevec is not perfect. It is expensive, costing about $25,000 a year.

It is not a cure: some cancer cells remain lurking, quiescent and

ready to spring if the drug is stopped, so patients must take it every

day for the rest of their lives. And some patients are now developing

resistance to Gleevec.

Still, Dr. Sawyers says, " Seven years later, most of our patients are

still doing well. " Without Gleevec, he added, most would be dead.

As for the future of cancer therapy, Dr. Golub and others say that

Gleevec offers a taste of the possible.

Dr. Golub said he expected that new drugs would strike the Achilles'

heels of particular cancers. The treatment will not depend on where

the cancer started - breast, colon, lung - but rather which pathway is

deranged.

" It's starting to come into focus how one might target the problem, "

Dr. Golub said. " Individual cancers are going to fall one by one by

targeting the molecular abnormalities that underlie them. "

And some cancer therapies may have to be taken for a lifetime, turning

cancer into a chronic disease.

" Seeing cancer become more like what has happened with AIDS would not

be shocking, " Dr. Golub says. " Does that mean cure? Not necessarily.

We may see patients treated until they die of something else. "

That is what Mr. Weinstein hopes will happen with him. The cancer is

still there: new, exquisitely sensitive tests still find a few cells

lurking in his bone marrow. And Gleevec has caused side effects. Mr.

Weinstein says his fingers and toes sometimes freeze for a few

seconds, and sometimes he gets diarrhea.

But, he said, " Certain things you put out of your mind because life is

so good. "