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A drug’s unintended use restores the gift of hearing

Edith Garrett’s hearing, which was nearly gone in 2006, has been restored in one ear. Edith Garrett’s hearing, which was nearly gone in 2006, has been restored in one ear. (Gregory Smith for The Globe via Ap)
By Stephen Smith
Globe Staff / July 9, 2009
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It was the honeyed drawl of her professor that first pierced the silence enveloping Edith Garrett for an entire year, since the day she had lost her hearing. But she dismissed it, thinking she was just having a good day. That was until she was woken from her nap later that November afternoon by a racket from a neighbor’s apartment.

“I said, ‘What is that?’ My roommates looked at me, and they said: ‘It’s the dog barking downstairs. It’s been there since August when we moved in,’ ’’ Garrett recalled.

Today, Garrett’s hearing is near-perfect in one ear, her rare neurological ailment treated by a drug called Avastin. But the wonder here isn’t simply that her hearing has been restored. The real wonder is how.

Garrett’s recovery, highlighted yesterday by researchers at Massachusetts General Hospital, represents a powerful tale of scientific discovery that illustrates how millions of dollars in spending and years of research into a drug - in this instance, Avastin, approved to treat late-stage colon, breast, and lung cancers - can yield a treatment for seemingly unrelated diseases.

For rare conditions, finding unintended uses for off-the-shelf drugs is often the best approach - saving time and money - because the potential financial payoff for a new medication is too little to attract interest from big drug companies.

The beneficiary in this case was Garrett. As a 19-year-old college student, she was diagnosed with neurofibromatosis type 2, which causes tumors to sprout inside the brain. Traditionally, as the tumors engulf nerves that regulate hearing, balance, swallowing, and other vital functions, patients are left with two options: surgery and radiation, both with worrisome complications.

Mass. General researchers’ findings on the unexpected value of Avastin, chronicled online yesterday by the New England Journal of Medicine, are preliminary. Researchers warn the drug is not a cure for the condition, most often diagnosed when people reach their 20s and estimated to afflict about 12,000 Americans. But it offers a shard of promise for patients often left hopeless by the rarity of their disease.

“We really felt we stood on the shoulders of the oncology community,’’ said Dr. Scott Plotkin , director of Mass. General’s Neurofibromatosis Clinic and lead author of the study. “Our goal was to build on the scientific successes to date and not to have to go back to square one.’’

Neurofibromatosis type 2 - known in medical shorthand as NF-2 - typically arrives with quiet stealth. During high school in Atlanta, Garrett experienced bouts of facial paralysis. “I just thought I had a crooked smile,’’ Garrett said.

But then, as she was starting her sophomore year at Rhodes College in Memphis five years ago, she noticed a small, painful protrusion on her shin. Tests ultimately revealed that the bump on her leg was a harbinger of the genetic ailment already spawning tumors inside her brain.

One night, prowling the Internet for details, Garrett discovered something that stunned her: Patients with the tumors frequently lose their hearing.

“I called and I asked my mom, ‘Am I going to go deaf?’ And she said, ‘We just don’t know.’ ’’

Without realizing it, Garrett had already lost hearing in her right ear. She had begun, unconsciously, compensating for that deficit, something doctors have witnessed in other patients. When she strolled into a classroom, she later realized, she would veer toward desks on the right side - so that her left ear could hear the instructor. When her cellphone jangled, she would always put it to her left ear.

In the language of doctors, the tumors caused by the condition are considered benign, because their cells lack the capacity to rapidly and destructively divide, a key trait of malignant cancers. But the complications that can result from neurofibromatosis are anything but benign.

“NF-2 is a disorder that’s like fighting a forest fire,’’ said Dr. Dade Lunsford, a University of Pittsburgh Medical Center neurosurgeon. “What you try to do is put out the fire that’s burning at that moment. So if there’s a hearing nerve tumor that’s getting bigger and causing pressure on the brain, normally we try to do surgery.’’

But both surgery and radiation can exact a toll. Operations on patients with tumors as large as limes - like those enmeshed with Garrett’s hearing nerves - almost always result in deafness. And while radiation can stop tumors from growing, it can spur scarring and may cause cancer.

That is why researchers had long been eager to find some other way to tame the tumors. Traditional chemotherapy seemed unlikely to help because it targets those rapidly dividing cells that aren’t found in benign growths.

Newer drugs, pioneered by Boston scientists, aim at a different pathway, known as angiogenesis. Those medications starve cancerous tumors of the blood they need by disrupting blood vessels spawned by the tumor. But it wasn’t clear - until now - that the benign tumors of neurofibromatosis type 2 patients had the ability to grow those vessel networks.

By using old tissue samples, the Mass. General researchers showed that the tumors are indeed associated with excess blood vessel development. So the scientists decided to give 10 patients Avastin, one of the new class of angiogenesis inhibitors.

Garrett’s hearing declined precipitously in December 2006; before taking the medication, she scored 8 percent on a standard hearing test known as word recognition. Now, she stands at 98 percent in one ear, but still lacks hearing in the other.

“You’re lucky as a physician,’’ Plotkin said, “to see a response like this once in your career.’’

Of the 10 patients in the study, the tumors of six shrank by 20 percent or more, with the reduction lasting 11 to 16 months so far. Seven patients had hearing loss prior to treatment, and after taking Avastin, the hearing of six either improved or remained stable. The patients experienced some side effects from the drug, including high blood pressure and liver toxicity, but none was considered severe.

Lunsford, who was not involved in the research, described the findings as “extraordinarily preliminary data,’’ but added that the study “offers a glimmer of hope, and it certainly warrants further exploration.’’

It remains unclear, for example, whether patients would need to take the drug regularly or if they could stop and start. The Boston scientists are looking for financing to expand their research to other centers.

Garrett isn’t taking Avastin at the moment because she underwent surgery in June designed to ease her facial paralysis. Still, she’s well enough that she’s preparing to start a new job.

In the fall, she will begin teaching high school math in Atlanta - at a school for hearingimpaired children.

Stephen Smith can be reached at stsmith@globe.com.