Dear Henry

This is about FA. Dr. D'Andrea is a good guy. He came to Aunt Abby's house and spoke to all of our friends when we had our first fundraiser. His sister happened to live down the street.



Link Between Cancer, Birth Defects
Though Not Fully Understood, Connection Is Already Prompting Clinical Trials, Treatment Shifts

By AMY DOCKSER MARCUS

Staff Reporter of THE WALL STREET JOURNAL

April 20, 2004; Page D1

In the search for a cure for cancer, researchers have made an intriguing discovery: Many well-known cancers have much in common with rare childhood diseases.

The findings are already prompting new clinical trials testing the same drugs in cancer patients and people born with rare diseases. The hope is that drugs that shrink tumors in people with cancer will also help children with rare diseases. For those children, the drugs could be given early in life, possibly even shortly after birth, potentially eradicating or drastically changing the course of illnesses now considered incurable.

Cancer researchers have long suspected a connection with rare childhood diseases, in part because some of the same processes that are important in the normal development of an embryo go awry when a tumor develops. Only recently, though, have scientists figured out the various pathways on which certain genes sit. That in turn has led to drug trials and new ways of diagnosing and treating diseases.

"If you can understand the genetic basis of these rare childhood diseases," says Alan D'Andrea, a Harvard Medical School professor and chief of the lab of radiation and cancer biology at Dana-Farber Cancer Institute in Boston, "you can learn about cancer in the general population."

In the past few years, researchers have discovered that some of the same genes that cause breast cancer and ovarian cancer in adults are responsible for causing Fanconi anemia in children. Fanconi anemia is a rare genetic disease in which children are born with thumb abnormalities and the blood disorder anemia that eventually leads to bone-marrow failure. Breast cancer and prostate cancer involve mutations at different sites along the same pathway as the genes for neurofibromatosis, a genetic disorder that causes developmental abnormalities in children. And the genes that cause tuberous sclerosis complex, a congenital disease resulting in neurological degeneration in children, sit on a common cancer genetic pathway.

While the early discoveries are tantalizing, the full implications of the research remain unknown. But the research is starting to transform the way doctors care for patients. Instead of grouping together diseases because they share similar sets of symptoms, treatments increasingly are based on the fact that certain diseases share "common disease pathways," says David Franz, founder of the Tuberous Sclerosis Clinic at Cincinnati Children's Hospital Medical Center. He is running a clinical trial in patients with that disease using the drug rapamycin.

At present, only adults who were born with the disease are enrolled in the trial. But if the drug appears to ameliorate or even reverse some of the symptoms, then eventually children could be treated with it "as early as possible" before their organs are destroyed, says John J. Bissler, a doctor involved with the trial at Cincinnati Children's Hospital. This would allow them the possibility of living a normal life. Dana-Farber Cancer Institute in Boston is planning trials using this same drug to treat leukemia patients and people suffering from gastrointestinal stromal tumors.

Ariad Pharmaceuticals Inc. in Cambridge, Mass., developed a drug to shrink cancer tumors. The drug, called AP23573, is now being tested in cancer patients. But it's also being tested to see if it can benefit children with the genetic disease tuberous sclerosis complex. Ariad and the Rothberg Institute for Childhood Diseases are testing the drug on human tissue cells that have the genetic defect associated with tuberous sclerosis complex, which affects one in 6,000 births. Jonathan Rothberg of the Rothberg Institute, which developed the tissue cells, says that by understanding tuberous sclerosis complex better, "we can change the life of a child and also have a chance of winning the war on cancer."

There are also intriguing links emerging between breast cancer and Fanconi anemia after it was determined that BRCA2, one of the best-known genetic markers for breast cancer, is a Fanconi anemia gene too. Fanconi anemia, a rare genetic disease, is often associated with birth defects like thumb and arm abnormalities.

Harvard's Dr. D'Andrea says this discovery has already had diagnostic implications for women with breast cancer. At Dana-Farber, women with breast cancer are now tested for mutations in one of at least seven Fanconi anemia genes that sit in the same pathway as the BRCA2 gene.

When doctors went back to the parents of children with Fanconi anemia and started investigating the health histories of family members, they found that there was often a higher incidence of breast cancer. "Up until that point, doctors would ask if anyone in your family had a history of breast or ovarian cancer to determine possible risk," says Dr. D'Andrea. "But they didn't ask if there were any children in the family with birth defects. We will now have more diagnostic markers for cancer."

For doctors treating children with rare diseases, the connection to something more prevalent like cancer has brought the potential for new attention from drug companies.

Allan Rubenstein, who treats patients with neurofibromatosis, set up a company, NexGenix Pharmaceuticals LLC, to test drugs and compounds useful in treating breast, prostate and other cancers on tissue and animal models with the genetic defect associated with neurofibromatosis. NexGenix's founders include prominent cancer researchers, such as Tyler Jacks, director of the Center for Cancer Research at the Massachusetts Institute of Technology, who made some of the initial discoveries linking the rare childhood disease to a common cancer pathway.

"We're trying to make it clear to the biotech world that they may be looking for a drug to treat breast or lung cancer, but that they would also have a niche in another market that is not small by any means," says Dr. Rubenstein, who estimates that neurofibromatosis affects more than 80,000 Americans.

One of the frustrations of the new research is that it has so far proved to be more helpful to cancer patients than to children born with rare defects. At St. Jude's Research Hospital in Memphis, Tenn., studies of children born missing a protein that repairs DNA damage have led to efforts to try to stimulate the same protein in people who do have it so that their normal cells repair DNA damage better. This may prevent cancer in people who are at higher risk of getting it.

But researchers haven't yet come up with a way to treat children with the disease ataxia-telangiectasia, who end up in wheelchairs because their muscles get progressively weaker. The same is the case for children with Fanconi anemia, where research is making a difference for breast-cancer patients but has not led to a new therapy for the children, many of whom do not reach adulthood. "This has not yet kicked back information in a positive way to these children," says Dr. D'Andrea, "but we keep trying."