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Discovery of cancer remedy raises issues of when, how to proceed

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Kelley Oliver Douglass, her daughter Maryn and their dog Cleveland. Mrs Douglass, 51, and her children carry a Pten mutation. Now, researchers have stumbled on a way to counter it - and the treatment may be as close as the local drugstore. Or eating 2.7 kg of Brussels sprouts a day - raw.

New York

WHEN Kelley Oliver Douglass got breast cancer, a genetic counsellor posed an odd question: Do you and your children have trouble finding hats that fit?

They did, and that gave the counselor a clue to the source of the cancer: a mutation in a gene called Pten. In addition to increasing head circumference, this rare mutation markedly raises the risk for several cancers, including prostate and breast cancer (the lifetime risk in carriers is 85 per cent), as well as autism and schizophrenia in some individuals.

Mrs Douglass, 51, of Mount Dora, Florida, and her children carry a Pten mutation. Now, researchers have stumbled on a way to counter it - and the treatment may be as close as the local drugstore.

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In a study published on Thursday in the journal Science, researchers found evidence that a compound called indole-3-carbinol (i3c) blocks an enzyme that inhibits the activity of Pten. With the gene more active, patients with the mutation may be better protected against cancer. They could get more i3c simply by eating Brussels sprouts, broccoli or other cruciferous vegetables.

But to get enough, they would have to eat a lot: six pounds (2.7 kg) of Brussels sprouts a day - raw. Yet i3c is widely available as a dietary supplement, and experts are debating whether to embark on a clinical trial with it. The new study was done only in mice and in human cancer cells grown in Petri dishes. The findings only apply to Pten gene activity - there is little evidence for most of the other wild claims made for i3c by supplement-makers. Inherited Pten mutations are rare, striking 1 in 200,000.

If the research holds up, however, it could be important to larger numbers of cancer patients. The mutation is not just inherited; the Pten gene is spontaneously mutated in many tumours. When that happens, the patient's prognosis is poor. Pten activity is somewhat impaired in the vast majority of human cancers. A drug that reactivates the gene could help curb cancer growth.

Mustafa Sahin, an expert on the Pten gene at Boston Children's Hospital, called the new research a "tour de force study". The result is "a paradigm shift in the field and very exciting in terms of its therapeutic implications," Dr Sahin, who was not involved in the research, wrote in an e-mail. Pier Paolo Pandolfi, senior author of the paper and director of the cancer centre at Beth Israel Deaconess Medical Center in Boston, has spent years trying to find a way to restore Pten activity.

The gene governs production of an enzyme that stops cells from dividing too quickly, reducing the chances that cancers will form. With reduced activity in Pten, cells grow uncontrollably. Pten mutations do not completely halt the gene's functions. Instead, the mutations tamp down the gene's activity, so cells make less of the enzyme needed for orderly growth.

But one of the hardest things for researchers to do is to find a way to increase, rather than turn off, a gene's activity. Eventually, Dr Pandolfi and his colleagues learnt enough about the Pten system to reason that i3c might do the trick.

"We got lucky, or smart," he said. Dr Pandolfi and his colleagues tested their treatment on human prostate cancer cells and in mice bred to develop prostate cancer. It worked: In the cells and in mice, i3c treatment resulted in fewer cancers, and those that arose were small and less deadly.

The findings, while intriguing, raise a difficult question for people with Pten mutations: should they run to the drugstore and buy i3c, hoping it will lower their cancer risk? Should cancer patients who have developed Pten mutations do so? Or should everyone wait for rigorous clinical trials with a pharmaceutical-grade version of i3c?

Dr Pandolfi posed those questions to several patient advocacy groups.

All agreed that a clinical trial is necessary. But some urged waiting for a drug company to make a more potent compound. If a trial with a supplement fails, no one will want to try again, some patients worry. Others want to go ahead immediately with a trial using an i3c compound made so its purity and potency are assured.

Kristin Anthony, president and chief executive of Pten Foundation, has the gene mutation and so does her 16-year-old daughter. Wary of taking a drugstore supplement and hoping for the best, she is urging that experts begin a clinical trial now with a pure form of i3c.

If the results are at all promising, she hopes a drug company might develop and test a more potent form. For her part, Mrs Douglass is doing all she can to protect herself and her children from cancer. She had her unaffected breast removed prophylactically and also had a prophylactic hysterectomy. A CT scan found an early-stage kidney cancer, so she had part of her kidney removed. She has frequent colonoscopies to check for colon cancer and skin exams to look for melanoma. Her 20-year-old daughter will soon be having mammograms, as is recommended for young women with inherited Pten mutations.

"A clinical trial could literally change my children's lives," Mrs Douglass said. "I would totally enter a clinical trial." In the meantime, she said, "I will eat more broccoli." NYTIMES