Down Syndrome May Hold/WSJ

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Down Syndrome May Hold

Clues to Fighting Cancer

Researchers Probe Why Those With Disorder Are Less Likely to Develop

Certain Tumors

By AMY DOCKSER MARCUS

Staff Reporter of THE WALL STREET JOURNAL

September 6, 2005

Researchers are working to unravel a medical mystery that they hope

will lead to new ways to fight cancer: They're trying to figure out

why people with Down syndrome are less likely to get certain common

cancers than the general population, and why they respond better to

treatment in other cancers.

Recent research shows that people with Down syndrome, a genetic

condition with a range of physical and intellectual disabilities, have

a significantly lower-than-expected rate of breast cancer, lung

cancer, mouth cancer and other common solid tumors. They are at

significantly greater risk of getting a rare type of leukemia, called

acute myeloid leukemia (AML), when they are children -- but they have

a substantially higher survival rate and lower relapse rate than

children in the general population.

Now, studies are being done at Children's Hospital Boston, s

Hopkins University School of Medicine, the University of Chicago, the

Barbara Ann Karmanos Cancer Institute in Detroit, and other centers

around the country, to find out why this is. By understanding the

various characteristics of Down syndrome that relate to cancer,

researchers hope to develop new cancer drugs, and identify specific

targets for cancer treatments, that will benefit all patients.

" Individuals with Down syndrome, who are too often viewed as a burden

on society, have in fact provided us with a major clue that is

fundamental to the health of everyone, " says H. Reeves,

professor at the s Hopkins University School of Medicine, who is

studying mice to understand how Down syndrome has a protective effect

against cancer.

Researchers believe the answers they're seeking lie deep in people's

genetic makeup. Much of the research is focused on Chromosome 21. Most

people with Down syndrome have three copies of Chromosome 21 compared

with only two in the general population. This extra copy is believed

to be responsible for many of the disabilities associated with Down

syndrome, such as language and cognitive deficits. But people with

Down syndrome also make more of the proteins associated with that

chromosome -- including a substance known as endostatin that may be

involved in preventing cancer.

In the case of acute myeloid leukemia, efforts center around a genetic

mutation that appears to be found exclusively in AML patients who have

Down syndrome. Some scientists say this mutation makes the children

more responsive to the chemotherapy drugs used to treat it. The

Children's Oncology Group, a consortium of pediatric cancer centers in

the U.S. and Canada, is following over 200 children with Down syndrome

for five years who are being treated for or have had leukemia hoping

to find new insights into why.

Not everyone agrees that there is something intrinsic to Down syndrome

that protects people from cancer. It may simply be that this

population isn't being adequately screened for cancer so the disease

may be more likely to be undetected in people with Down syndrome than

the general population.

There also is some concern that if a drug is designed to prevent

cancer by mimicking levels of certain proteins found in people with

Down syndrome, this might reproduce some of the other aspects of Down

syndrome, such as learning and memory problems. Ryeom, a

research associate at Children's Hospital Boston who is studying

aspects of Chromosome 21, says that if researchers develop a potential

drug, they plan to run learning and memory tests first on mice before

going further.

The focus on the connection to cancer comes at a time of growing

interest in research into Down syndrome. The life expectancy for

people with Down syndrome has risen dramatically in the past decades,

from an average age of 25 in 1983, to an average of 56 today, in part

because of earlier intervention for health problems. That means

researchers can now afford to turn their attention to improving the

lives of people with Down syndrome, including boosting their cognitive

abilities.

It also means that they are living long enough to get diseases like

cancer that mainly affect older people. For a long time, oncologists

suspected that people with Down syndrome were at lower risk for

cancer. Several studies published in the past few years seem to have

confirmed it: The studies examined death certificates in the U.S., and

health, hospital and cancer registries in countries like Denmark,

Sweden and Australia, and found that the number of solid-tumor cancers

were lower than expected for people with Down syndrome.

" The lower incidence of cancer used to be explained by saying people

with Down syndrome didn't live long enough to get cancer, " says Judah

Folkman, who heads the vascular biology program at Children's Hospital

Boston. " Now they are living long enough to get it but still aren't

and that's intriguing. "

Research led by a group of scientists at Beth Israel Deaconess Medical

Center in Boston found a possible clue in endostatin, a fragment of a

protein found on Chromosome 21. Endostatin appears to damp the

development of new blood vessels that feed tumors. And people with

Down syndrome have around 1.7 times the endostatin in their body

fluids and tissue than typical individuals. Using mice that they

manipulated to produce endostatin at levels comparable to those in

people with Down syndrome, the researchers then put cancer tumors into

the mice. They found that the rate of tumor growth in these mice was

reduced by threefold compared to mice that had regular levels of

endostatin.

The finding raises the possibility of someday finding a way to elevate

the levels of proteins that people make naturally in their bodies as a

way of " controlling the progression of the cancer so that survival

increases without increasing the toxicity that is associated with

cancer therapies, " says Raghu Kalluri, director of the Center for

Matrix Biology at Beth Israel and the study's lead author.

Dr. Folkman's lab is also collaborating with scientists at Genentech

Inc., a maker of cancer drugs, on a project to study a gene found on

Chromosome 21 called " Down syndrome critical region 1 " (DSCR1) that

could be a possible new focus for developing cancer drugs. The

researchers at Children's Hospital Boston believe the DSCR1 gene and

endostatin together protect people with Down syndrome against cancer.

The interest in people with Down syndrome isn't limited to cancer.

Researchers are also working with Dr. Folkman's lab to try to

understand whether endostatin is also responsible for why people with

Down syndrome appear to have lower blood pressure and less

athlerosclerosis -- or buildup of plaque in the arteries -- than those

in the general population. Doctors at Cedars-Sinai Medical Center in

Los Angeles are launching a study later this year using electron beam

computed tomography (CT) scans to examine the arteries of people with

Down syndrome. " We believe that some of the same genes that lead

individuals with Down syndrome to have congenital heart problems at

birth might be protecting them later in life from cardiovascular

calcified plaques, " says R. Korenberg, a professor of pediatrics

and human genetics at the University of California in Los Angeles, who

is leading the study.

Martha Linet, chief of the radiation epidemiology branch at the

National Cancer Institute and the co-author on a 2003 study looking at

the records of people with Down syndrome in Sweden and Denmark, sounds

a note of caution regarding all this research. The findings have been

based on numbers that were still relatively small, she says. Even in

her own large study of more than 4,800 people in two countries, Dr.

Linet said, " the total number of solid tumors in this whole study was

28. You have to be careful what you say about 28 cancers. "