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Drugs aim to make several cancers self-destruct

Great uncertainties remain, but such drugs could mean new treatment for rare cancers as well as common ones
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First Published: Sun, Dec 23 2012. 10 28 PM IST
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. Photo: C.J. Gunther/NYT
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. Photo: C.J. Gunther/NYT
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 tumour growth. Many scientists see this as the beginning of a new genetic age in cancer research.
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 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 fundraising for particular cancers to pushing for research aimed at many kinds of cancer at once, 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 tumour was wrapped around a cord that connects the testicles 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 tumours 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, New Jersey.
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, 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, Debussche, saying, “Laurent, I have a problem.” He confessed that he had treated some of the mice only once. And their tumours had vanished.
Debussche was stunned. “We have to reproduce it,” he said. They did.
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. ©2012/THE NEW YORK TIMES
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First Published: Sun, Dec 23 2012. 10 28 PM IST
More Topics: Cancer | liposarcoma | Sanofi | Merck | Roche |