A new approach to treating cancer

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http://www.post-gazette.com/pg/06095/679689-114.stm

A new approach to treating cancer

Wednesday, April 05, 2006

By Amy Dockser Marcus, The Wall Street Journal

Cancer has long been defined by where it is found in the body. Patients

have

breast cancer, prostate cancer, lung cancer.

In a significant shift, researchers are coming to believe that cancer

comprises hundreds of subgroups based more on genetic makeup than

location.

This new thinking means that instead of focusing cancer treatment on

organs,

the emphasis increasingly is going to be on finding the specific genetic

changes driving an individual's cancer and targeting them with drugs.

Some

people who have cancers in different organs may end up taking the same

drugs

because common genetic mutations are involved.

Already, researchers have identified a number of genetic variations,

resulting in some of the most exciting breakthroughs in oncology:

Doctors

now believe that the drugs Tarceva and Iressa work best in a certain

subgroup of patients with lung cancer, Gleevec in particular subtypes of

leukemia and sarcoma patients, and Herceptin in certain breast-cancer

patients. Cancer researchers also continue to announce discoveries of

new

cancer subtypes in liver, brain and prostate cancer, among others.

Such subtyping is a very different approach from the way doctors

currently

classify cancer. In order to make a diagnosis, pathologists examine the

shape and pattern of cells under a microscope, searching for patterns

that

are associated with broad subcategories (such as non-small-cell lung

cancer). But now, researchers are using more sophisticated technologies

to

explore each cancer's unique gene pattern. With advances such as

sequencing

the DNA of a tumor, they can look for changes or mutations that might

then

be targeted with drugs. The goal is to develop tests to identify such

variations in patients, and treat them, no matter what organ the cancer

is

in.

The National Cancer Institute and the National Human Genome Research

Institute, both part of the National Institutes of Health, are spending

$100

million over three years to do a pilot project of the Cancer Genome

Atlas,

which will attempt to characterize genetic mutations in cancer. The

Institute of Medicine just set up a committee to explore clinical

applications of these and other discoveries. The group is expected to

produce a consensus report with recommendations next year.

More trials are opening based on a cancer's genetic subtype -- such as

studies of how a gene known as MGMT may affect response to a treatment

for a

brain cancer. Also, commercial tests are available to identify

mutations,

such as a $975 test from Genzyme Genetics, a division of Genzyme Corp.,

to

see if patients have a genetic mutation that makes them likely to

respond to

Tarceva or Iressa. Different tests are available from the Molecular

Profiling Institute in Phoenix and others. And more are being developed.

The new approach involves a number of challenges. In the case of some of

the

new discoveries, there aren't drugs yet to target the subtypes, meaning

the

new information won't yet make a difference in treatment. The

technologies

that make subtyping possible, such as techniques for examining a

thousand

genes in a cancer all at once, are costly, and it will require large

sums to

get information on every cancer.

There also are concerns that researchers would spend large amounts of

time

and money developing drugs that might help only a small group of people.

Even in more common cancers such as lung cancer or breast cancer, just a

fraction of patients may share common genetic mutations and respond to

drugs

targeted against them.

Some researchers, including Bruce E. , director of the Carole M.

and

Philip L. Lowe Center for Thoracic Oncology at the Dana-Farber Cancer

Institute in Boston, argue that by targeting subgroups rather than

searching

for a cure for everyone that has so far proven elusive, doctors may have

a

better chance of ultimately curing more people. The idea isn't to treat

everyone the same and end up with drugs that make many people " only 20

percent better, " says Dr. , one of the patent-holders on a test

to

subdivide lung-cancer patients. " Instead, we'd like to start making 20

percent of the people 100 percent better. "

It is also possible that because a genetic variation may cut across

various

organs, a tailored drug could be used more broadly. For instance,

Novartis

AG's Gleevec is approved to treat subgroups of two different cancers,

gastrointestinal stromal tumors and chronic myelogenous leukemia. Now

Novartis says Gleevec is also effective for four other diseases,

including

certain blood cancers and a kind of skin tumor.

For some patients, subtyping already is making a difference. In July

2004,

Marguerite Blattner, now 53, was diagnosed with stage 4 lung cancer. As

a

female who had never smoked, the La Jolla, Calif., woman had

characteristics

that could make a difference in her prognosis. Still, she found she was

" thrown into this big pool where you're just one of hundreds of

thousands of

people with lung cancer. You're not differentiated in any way by who you

are, " she says.

She saw Dr. at Dana-Farber, who recommended that she get her

tumor

tested to see if she had a mutation that would make her likely to

respond to

Tarceva or Iressa, which have far fewer side effects than chemotherapy

because they target only cancer cells, not normal ones.

" The doctor called me and said, 'Congratulations, you have the

mutation,' "

Ms. Blattner says. Instead of doing standard chemotherapy first, Ms.

Blattner quickly went on Iressa. She still is on the drug and has had

such

minimal side effects, she said, " that I can't even categorize myself

like

other lung-cancer patients who get chemo. "

Last year, in a paper published in the New England Journal of Medicine,

researchers announced they were starting to understand why some patients

with glioblastoma multiforme, a brain cancer, are likely to live longer

if

they are treated with the drug temozolomide. One of the keys was a gene

known as MGMT, which is involved with DNA repair. In 60 patients in whom

the

gene was active, two-year survival was just 13.8 percent after treatment

with temozolomide and radiation. For 46 patients in whom the gene was

" silent, " treatment was much more effective, and two-year survival was

46

percent. The trial was organized in seven countries by the European

Organization for Research and Treatment of Cancer and the National

Cancer

Institute of Canada Clinical Trials Group.

Schering-Plough Corp., the maker of temozolomide, and Oncomethylome

Sciences

are now developing technology to measure the status of the MGMT gene in

patients with glioblastoma. There are new trials targeting patients with

the

silenced gene, as well as for patients with an active MGMT gene to find

ways

to overcome their resistance to the drug. Some groups are also

considering

research into whether the MGMT gene plays a role in lung-cancer

patients.

Some researchers have questioned the move toward launching trials open

only

to people with particular subtypes -- arguing that trials open to people

with cancer in the same organ was how smaller groups were first

discovered.

The subgroups were ones who didn't respond like the other patients.

Warren Mason, a neuro-oncologist at Princess Margaret Hospital in

Toronto

and one of the co-authors of the glioblastoma paper, says that such

trials

don't necessarily mean that other patients with the same disease

shouldn't

have access to a targeted drug. " I don't think there is enough evidence

to

say that some people with glioblastoma should not get temozolomide, " he

says. " It's the only drug we have that's effective for it, and even if

it is

only helping some people a little, that's important in a lethal cancer. "

One of the most frustrating aspects of research into subtypes is the

lack of

drugs to target what researchers are finding, says Bert Vogelstein, an

investigator at the Medical Institute and director of the

Ludwig

Center for Cancer Genetics and Therapeutics at s Hopkins University.

Dr. Vogelstein's lab found that a particular gene called PIK3CA was

mutated

in about one-third of colon cancers. The mutation increases the activity

of

an enzyme, and drugs could theoretically be developed to inhibit the

enzymes. Investigators at other institutions have found that the

mutation

also appears in a " significant fraction " of brain, ovarian, breast and

liver

cancers, says Dr. Vogelstein, meaning that " it's a perfect target for

drug

development. "

Still, turning a tantalizing discovery into a useful drug " could take 10

years, and that's being optimistic, " he says.