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From Infamy to Therapy
How the most reviled drug in history became a cancer treatment.

 

Angiogenesis in action
When Dr. Robert D'Amato stumbled on thalidomide, no one knew why it caused birth defects. D'Amato solved the mystery by showing that the infamous drug inhibits the growth of blood vessels.

 

 

DEVIL IN DISGUISE
1950 Thalidomide is widely prescribed in Europe, Canada, Australia, Asia, Africa, and South America as a sedative and anti-morning sickness drug. Fortuitously, the drug isn’t marketed in the U.S.

"Everyone thought it was ridiculous to work with thalidomide. People would say 'No one would take that drug.'" -Robert D'Amato, MD

DAMAGE DONE
1961 An Australian physician reports in The Lancet, a British medical journal, that nearly 20 percent of women taking thalidomide during pregnancy had babies with multiple severe abnormalities. The drug is pulled from the market, but the damage has been done—as many as 10,000 babies have been born with stunted limbs, horrifying the world.

A NEW IDEA
1971 At Children's Hospital Boston, Judah Folkman, MD, publishes a landmark paper in The New England Journal of Medicine, presenting his hypothesis that cancerous tumors require a blood supply—and dedicated blood vessels—to nourish them. Folkman theorizes that if angiogenesis, or growth of new blood vessels, could be halted, tumor growth would also stop.

Robert D'Amato, MD

EYEING A SOLUTION
1992 Ophthalmologist Robert D'Amato, MD, joins Folkman's lab, hoping to study the biology of age-related macular degeneration, an eye disease that can lead to blindness. Like cancer, macular degeneration is thought to be a problem of uncontrolled blood-vessel growth—in this instance, in the retina.

A TOP-TO-BOTTOM SEARCH
1993 D'Amato sets out to find new angiogenesis inhibitors. He attacks the problem in a novel way—by taking a survey of his own body, starting at the top. D'Amato seeks areas where blood vessels continue to develop, and would be affected by a drug with anti-angiogenic properties. Then it occurs to him that in a woman’s body, blood vessels grow both during the menstrual cycle and in the developing fetus during pregnancy. So he searches for compounds that have been reported to stop menstruation and cause fetal malformations. Two drugs stand out. One, retinoic acid, is used for acne. The other is thalidomide. No one knows how it works, making it a perfect candidate for study, so D'Amato orders some thalidomide and begins testing it. He finds that it inhibits blood vessel growth in a rabbit’s eye, one of the lab’s standard tests for angiogenesis.

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A DARING PROPOSAL
1994 D'Amato publishes his results in a paper titled, "Thalidomide is an inhibitor of angiogenesis" in The Proceedings of the National Academy of Sciences, and faces a firestorm of criticism. All the old fears about fetal deformities resurface. D’Amato and Folkman convince Entremed, a small biotech company, to support the work, and thalidomide enters clinical trials for age-related macular degeneration and for brain tumors. Investigators must follow a strict protocol laid down by the FDA to prevent birth defects—women enrolled in the trials must use two forms of contraception and undergo periodic pregnancy testing. All patients must register with the FDA, and physicians must take a course before being allowed to prescribe thalidomide.

LAST RESORT
1995 A New York cardiologist named Ira Wolmer is diagnosed with multiple myeloma—a fatal, hard-to-treat cancer of the bone marrow diagnosed in almost 14,000 people each year in the U.S. Nothing has worked for Wolmer's cancer. His wife, Beth, hears about Folkman and his theory that cancers can be treated by starving them of their blood supply. She calls Folkman, who suggests trying thalidomide. Her husband's oncologist, Dr. Bart Barlogie of the Myeloma and Transplantation Research Center at the University of Arkansas, initially dismisses the idea as ridiculous, but Folkman convinces him that angiogenesis inhibitors could work in multiple myeloma.

GLIMMER OF HOPE
1997 Children's Intellectual Property Office, working closely with D'Amato, gets thalidomide patented for use as an angiogenesis inhibitor. The same year, Barlogie gets permission to test thalidomide in Ira Wolmer. Unfortunately, it doesn't work, and Wolmer dies the following year, but Barlogie tries it in a second patient, who has a near-complete remission of his cancer. Barlogie expands to a larger trial, involving 84 patients with advanced multiple myeloma who have not responded to previous therapy.

A STAMP OF APPROVAL
1998 Entremed licenses thalidomide to Celgene, another small biotech company. The same year, the FDA grants Celgene approval to market thalidomide for the prevention and treatment of erythema nodosum leprosum, the disfiguring skin condition associated with leprosy. Today, this is still the only approved indication for thalidomide in the U.S.

Promising results continue to emerge for other cancers. In all, about 50 clinical trials of thalidomide or its related compounds are ongoing for cancer.

SPREADING THE NEWS
1999 Barlogie publishes the results of his multiple myeloma trial in The New England Journal of Medicine. One-third of the 84 patients show a response to thalidomide, and two remain in complete remission at 12 to 16 months of follow-up. This success spurs trials of thalidomide for multiple myeloma around the world.

ROAD TO REDEMPTION
2004 Celgene seeks FDA approval to market thalidomide for multiple myeloma. A dozen Phase III studies are underway around the world, with one-third to one-half of patients responding (see figure). The first complete results are presented in May at the American Society of Clinical Oncology annual meeting.