Drugs Aim to Make Several Types of Cancer Self-Destruct
C.J. Gunther for The New York Times
Dr. Donald Bergstrom is a
cancer specialist at Sanofi, one of three companies working on a drug to
restore a tendency of damaged cells to self-destruct.
By GINA KOLATA
Published: December 22, 2012 89 Comments
For the first time ever, three pharmaceutical companies are poised to
test whether new drugs can work against a wide range of cancers
independently of where they originated — breast, prostate, liver, lung.
The drugs go after an aberration involving a cancer gene fundamental to tumor growth. Many scientists see this as the beginning of a new genetic age in cancer research.
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Joe Bellino, shown with his daughter, had a rare kind of cancer that could respond well.
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Great uncertainties remain, but such drugs could mean new treatments for
rare, neglected cancers, as well as common ones. Merck, Roche and
Sanofi are racing to develop their own versions of a drug they hope will
restore a mechanism that normally makes badly damaged cells
self-destruct and could potentially be used against half of all cancers.
No pharmaceutical company has ever conducted a major clinical trial of a
drug in patients who have many different kinds of cancer, researchers
and federal regulators say. “This is a taste of the future in cancer
drug development,” said Dr. Otis Webb Brawley, the chief medical and
scientific officer of the American Cancer Society. “I expect the organ
from which the cancer came from will be less important in the future and
the molecular target more important,” he added.
And this has major implications for cancer philanthropy, experts say.
Advocacy groups should shift from fund-raising for particular cancers to
pushing for research aimed at many kinds of cancer at once, Dr. Brawley
said. John Walter, the chief executive officer of the Leukemia and Lymphoma Society, concurred, saying that by pooling forces “our strength can be leveraged.”
At the heart of this search for new cancer drugs are patients like Joe
Bellino, who was a post office clerk until his cancer made him too sick
to work. Seven years ago, he went into the hospital for hernia
surgery, only to learn he had liposarcoma, a rare cancer of fat cells. A
large tumor was wrapped around a cord that connects the testicle to the
abdomen. “I was shocked,” he said in an interview this summer.
Companies have long ignored liposarcoma, seeing no market for drugs to
treat a cancer that strikes so few. But it is ideal for testing Sanofi’s
drug because the tumors nearly always have the exact genetic problem
the drug was meant to attack — a fusion of two large proteins. If the
drug works, it should bring these raging cancers to a halt. Then Sanofi
would test the drug on a broad range of cancers with a similar genetic
alteration. But if the drug fails against liposarcoma, Sanofi will
reluctantly admit defeat.
“For us, this is a go/no-go situation,” said Laurent Debussche, a Sanofi
scientist who leads the company’s research on the drug.
The genetic alteration the drug targets has tantalized researchers for
decades. Normal healthy cells have a mechanism that tells them to die if
their DNA is too badly damaged to repair. Cancer cells have grotesquely
damaged DNA, so ordinarily they would self-destruct. A protein known as
p53 that Dr. Gary Gilliland of Merck calls the cell’s angel of death
normally sets things in motion. But cancer cells disable p53, either
directly, with a mutation, or indirectly, by attaching the p53 protein
to another cellular protein that blocks it. The dream of cancer
researchers has long been to reanimate p53 in cancer cells so they will
die on their own.
The p53 story began in earnest about 20 years ago. Excitement ran so
high that, in 1993, Science magazine anointed it Molecule of the Year
and put it on the cover. An editorial held out the possibility of “a
cure of a terrible killer in the not too distant future.”
Companies began chasing a drug to restore p53 in cells where it was
disabled by mutations. But while scientists know how to block genes,
they have not figured out how to add or restore them. Researchers tried
gene therapy, adding good copies of the p53 gene to cancer cells. That
did not work.
Then, instead of going after mutated p53 genes, they went after half of
cancers that used the alternative route to disable p53, blocking it by
attaching it to a protein known as MDM2. When the two proteins stick
together, the p53 protein no longer functions. Maybe, researchers
thought, they could find a molecule to wedge itself between the two
proteins and pry them apart.
The problem was that both proteins are huge and cling tightly to each
other. Drug molecules are typically tiny. How could they find one that
could separate these two bruisers, like a referee at a boxing match?
In 1996, researchers at Roche noticed a small pocket between the
behemoths where a tiny molecule might slip in and pry them apart. It
took six years, but Roche found such a molecule and named it Nutlin
because the lab was in Nutley, N.J.
But Nutlins did not work as drugs because they were not absorbed into the body.
Roche, Merck and Sanofi persevered, testing thousands of molecules.
At Sanofi, the stubborn scientist leading the way, Dr. Debussche,
maintained an obsession with p53 for two decades. Finally, in 2009, his
team, together with Shaomeng Wang at the University of Michigan and a
biotech company, Ascenta Therapeutics, found a promising compound.
The company tested the drug by pumping it each day into the stomachs of mice with sarcoma.
A week later, Cedric Barriere, the scientist conducting the experiment,
went to his boss, Dr. Debussche, saying, “Laurent, I have a problem.” He
confessed that he had treated some of the mice only once. And their
tumors had vanished.
Dr. Debussche was stunned. “We have to reproduce it,” he said. They did.
Dr. Debussche popped open a bottle of Champagne, but his team tempered its hope.
“The joke is if we were trying to cure mouse cancer we would have done
it 30 years ago,” said Dr. Donald Bergstrom, a vice president at Sanofi.
As research progressed, all three companies worried about the
unprecedented challenges of testing a drug in many types of cancers at
once. Such a clinical trial would most likely involve just a few
patients in each of many medical centers. But keeping a trial going
involves mounds of paperwork and documentation. Medical centers are
often loath to do it for just a handful of patients.
Roche was the first to start testing a p53 drug in patients. The company
began, as required, with an attempt to establish a dose strong enough
to be effective but not too toxic. It took a surprisingly long time —
three years — because Roche was cautious, starting with a tiny dose and
gradually escalating it.
Health authorities in the United States and Europe worried that the medicines might have unexpected effects.
“Drugs of this type had never been given to a human being,” Dr. Gwen Nichols of Roche said.
The studies looked only at safety, but Dr. Nichols said there were
encouraging hints that the drugs might be working. In biopsies and
scans, cancer cells appeared to be dying. Rigorous efficacy studies are
next. If they are successful, they will be followed by clinical trials
across cancer types.
More recently, Merck began its study to find a safe dose. It is
enrolling only patients with acute myelogenous leukemia, a cancer in
which p53 is almost always disabled by the blocking protein MDM2.
Once the company finds the best dose, it plans to give its drug to just
15 to 30 patients and look for efficacy. And if the drug fails to break
apart the two huge proteins and enable the angel of death to do its job?
“Then we will not bring the drug forward,” Dr. Gilliland said.
Sanofi is in much the same position. It just started its safety tests in
Europe. Medical centers in the United States will be added next year.
Like Merck, it will focus solely on patients who are most likely to
respond to its own drug — in this case, patients with liposarcoma like
Mr. Bellino.
Their tumors can be as big as a watermelon, says Dr. Andrew J. Wagner,
an expert at the Dana-Farber Cancer Institute and one of Mr. Bellino’s
doctors. They often start at the back of a patient’s belly, where they
go unnoticed unless the person is very thin. “There is a lot of space
back there,” Dr. Wagner explained. Surgeons try to remove the tumors,
but they usually grow back and spread.
Liposarcoma is so rare — only about 2,000 or so cases each year — that
no drugs have ever been specifically tested on patients with this type
of cancer. Mr. Bellino said over the summer that he hoped he could be
among the first to try it. When the call goes out for study subjects, he
said, “I will be waving my hands.”
But the test will come too late for him. He died from his cancer on Nov. 13.
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