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.
it was ridiculous to work with thalidomide. People would say
'No one would take that drug.'"
-Robert D'Amato, MD
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
EYEING A SOLUTION
| Robert D'Amato, MD
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.
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
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
A STAMP OF APPROVAL
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
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.
SPREADING THE NEWS
|Promising results continue to emerge for other cancers. In all, about 50 clinical trials of
compounds are ongoing for cancer.
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.