Genetic Gamble: Drugs aim to make different types of cancer self-destruction

Click Here! Great uncertainties remain, but such drugs could mean new treatments for rare cancers, neglected, as well as those municipalities. Merck, Roche and Sanofi are racing to develop their own versions of a drug they hope to restore a mechanism that normally makes it severely damaged the cells self-destruct and could potentially be used against half of all cancers.

--> No pharmaceutical company has ever conducted a clinical trial of a drug in patients who have many different types of cancer, researchers and federal regulators say. "This is a taste of the future in the development of cancer drugs," said Dr. Otis Brawley Webb, medical and Scientific Director of the American Cancer Society. "We expect the organ from which cancer will be less important in the future and the most important molecular target," he added.
And this has important implications for Philanthropy, cancer experts say. Support groups should move from fund-raising for cancers in particular to push for research aimed at many cancers at once, said Dr. Brawley. John Walter, chief executive officer of the leukemia and Lymphoma Society, agreed, 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 an employee of the post office until his cancer made him too ill to work. Seven years ago, he went to the hospital for a hernia surgery, only to learn that he had a rare cancer, liposarcoma of the adipose cells. A large tumor was wrapped around a wire that connects the testicle in the abdomen. "I was shocked," he said in an interview this summer.
Companies have long ignored liposarcoma, not seeing no market for drugs to treat a cancer that affects so few. But it's ideal for drug testing of Sanofi, because the tumors are almost always the exact genetic drugs problem was to attack — a merger of two large proteins. If the drug works, it should bring these tumors raging a setback. Then Sanofi would you test the drug on a wide range of cancers with a similar genetic alteration. But if the drug fails against liposarcoma, Sanofi grudgingly admit defeat. "For us, this is a go/no-go," said Laurent Debussche, a scientist from Sanofi leads drug company seeks.
The genetic alteration of drug targets has tantalized scientists for decades. Normal healthy cells have a mechanism that tells them to die if their DNA is damaged too badly for repair. Cancer cells grotesquely damaged DNA, so ordinarily you would self-destruct. A protein known as p53 that Dr. Gary Gilliland of Merck called Angel of death cell normally sets things in motion. But cancer cells deactivate p53, or directly with a mutation, or indirectly, by attaching the p53 protein to another cellular protein that blocks. The dream of cancer researchers has long been to revive p53 in cancer cells that die on their own. P53 's story began in earnest about 20 years ago. Excitement ran so high that, in 1993, Science magazine has anointed the molecule of the year and put him on the cover. An editorial gave the possibility of a cure for a dreaded killer in the not too distant future ".
Companies began hunting for a drug to restore p53 in cells where it has been disabled by mutations. But while scientists know how to block genes, they haven't figured out how to add or restore them. Researchers have tried gene therapy, adding good copies of the p53 gene in cancer cells. That did not work. Then, instead of going after the mutated p53 genes, they went after half the cancers that used the alternative route to disable p53 by blocking linking it to a known protein like MDM2. When they stick together the two proteins, the protein p53 doesn't work anymore. Maybe, the researchers thought they might find a wedge between the two myself proteins and raise their share.
The problem was that both proteins are enormous and cling tightly to each other. Drug molecules are generally very small. How could find one that would separate these two bruisers, like a referee in a boxing match? In 1996, researchers at Roche has noticed a small pocket between the colossi where a small molecule could slip and pry them apart. It took six years, but Roche found such a molecule and named Nutlin because the lab was in Nutley, NJ
But Nutlins didn't work as drugs because they were not absorbed into the body. Roche, Merck and Sanofi persevered, testing thousands of molecules.
At Sanofi, the stubborn avant-garde scientist, Dr. Debussche, maintained an obsession with p53 for two decades. Finally, in 2009, his team, along with Shaomeng Wang at the University of Michigan and a biotech company, Ascenta Therapeutics, found a promising compound. The company tested the drug every day pumping in the stomachs of mice with sarcoma.e

Stomach-Acid-Suppressing Drugs May Raise Risk of Death After Angioplasty

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TUESDAY, Nov. 17, 2009 (Health.com) — Heart patients who take certain stomach-acid-suppressing drugs to prevent gastrointestinal bleeding may be at increased risk of dying after a cardiac procedure, according to a study presented at the annual meeting of the American Heart Association (AHA) in Orlando.

Researchers at Mount Sinai Medical Center, in New York City, reported that patients who underwent angioplasty, a procedure to clear blocked blood vessels in the heart, were 30% more likely to die if they were taking proton pump inhibitors (PPIs).

It’s unclear whether the patients in the study who were prescribed these medications were sicker than those who weren’t, and thus more likely to die. The study's lead author, Joseph M. Sweeny, MD, a cardiologist at Mount Sinai, says that he will continue to follow current guidelines on prescribing PPIs, but that he will also be "very careful" in deciding which of his patients need to be on the drugs.

Before undergoing angioplasty, heart patients are typically prescribed blood-thinning drugs such as aspirin and Plavix, which increase the risk of stomach bleeding and ulcers. In a joint statement issued in 2008, the AHA, the American College of Gastroenterology, and the American College of Cardiologists indicated that PPIs could help prevent stomach bleeding in people at high risk.

But some experts have raised concerns that PPIs could make Plavix less effective because they block the action of enzymes that are crucial for metabolizing the blood-thinning drug. A number of studies have suggested that mixing the two drugs could be risky for patients, while others have not.

The study examined some 8,300 angioplasty patients who had had drug-secreting stents placed in their hearts to prop open narrowed blood vessels. In all, 17% of the patients were prescribed PPIs.

During the follow-up period, which lasted an average of two years, 602 patients died. When Dr. Sweeny and his colleagues broke patients into groups according to which PPI they were taking, they found that omeprazole (Prilosec) and pantoprazole (Protonix) were associated with an increased risk of death of 72% and 54%, respectively, in the years following the procedure.

Two other PPIs, esomeprazole (Nexium) and lansoprazole (Prevacid), were not associated with a greater risk of dying after the procedure. It’s not clear whether this means some PPIs were safer than others, says Dr. Sweeny.

“The numbers that I got were very dramatic,” Dr. Sweeny says. “You have to raise questions as to exactly what this is coming from.”

The findings need to be interpreted cautiously, he adds, because the patients who were taking PPIs may have been sicker to begin with. “What the clinical implications of this are right now I don’t know,” he says. However, the risk of death and complications after angioplasty is relatively low overall.

“The jury is still out regarding acid-suppressing medications and Plavix,” says Shoshana J. Herzig, MD, a researcher at Beth Israel Deaconess Medical Center and Harvard Medical School, in Boston, who didn’t participate in Dr. Sweeny’s study.

Because overall mortality in the current study was greater among the patients on PPIs, says Dr. Herzig, it’s definitely possible they may have been sicker in the first place.

Even so, she says, “I think that it’s fairly clear that in patients who are on Plavix and an acid-suppressing medication, we should evaluate whether they actually need that acid-suppressing medication.” Although PPIs usually aren’t intended to be taken indefinitely, patients often wind up staying on the drugs anyhow, she says.

At least in ICU patients, Dr. Herzig says, PPIs are prescribed too often, in large part because the ulcer drugs are viewed as very safe. However, she adds, rarer side effects do come to light when a drug is prescribed to millions of people.

Any patient who is prescribed a PPI, Dr. Herzig and Dr. Sweeny agree, should ask their physician why, and find out how long they need to take the medication.

At the American Heart Association's annual Scientific Sessions meeting, more than 20,000 cardiologists and other physicians from around the country give presentations on new research and on advances in the diagnosis and treatment of heart disease and stroke.

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