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

Strategies: Stocks and the Economy, Singing Different Tunes

AppId is over the quota
AppId is over the quota
“THE test of a first-rate intelligence is the ability to hold two opposed ideas in the mind at the same time, and still retain the ability to function,” F. Scott Fitzgerald wrote in 1936. He might have been describing the difficulties faced by current analysts of the financial markets.

The stock market roared through the first quarter of this year, yet most people believe that the economy isn’t really healthy.

That may not be a contradiction, but making sense of it may require some awkward mental gymnastics.

Certainly, the market’s recent rise has been spectacular. While stocks have dithered in April, the Standard & Poor’s 500-stock index returned nearly 30 percent from its low of last Oct. 3 through March this year.

Yet the economic picture has been mixed at best, with unemployment still above 8 percent and the gross domestic product growing at an estimated annualized rate of only 2.5 percent in the first quarter, according to the Wall Street consensus. The latest New York Times/CBS News poll last week found that unemployment and the economy remain the main concerns of most voters, 70 percent of whom said the economy is “very” or “fairly” bad. That was an improvement over October, when 86 percent said the economy was “very” or “fairly” bad, but it’s hardly upbeat.

This kind of dichotomy — market returns that may not accurately reflect the underlying economy — actually occurs rather often, and it poses a ticklish problem, both for professional money managers and for the rest of us.

For example, if you focus on the economy and find that it’s weak, you might think it wise to lighten the risk in your portfolio and concentrate on protecting your assets. On the other hand, if you focus on the market’s momentum and believe stocks are likely to keep climbing, you might try to ride that wave until it crests.

But if you look at both the economy and the market, and believe both that the economy is weak and that the market’s momentum is upward, you may not be entirely comfortable with any course of action. Yet if you’re fortunate enough to have money to invest, you must do something. In a report last week, Ned Davis, founder of Ned Davis Research, an investment research firm in Venice, Fla., put the problem this way: What’s more important, he asked, “being right or making money?” He lands squarely on the side of making money, and says stocks are likely to rise over the next six months or so. But he acknowledged that he must balance his short-term views against his longer-term convictions about the state of the economy.

As a “secular bear,” he says he is convinced that the economy is plagued by deep-seated maladies that will take years to clear up and that, at some point, the stock market will resume a long-term downward trend. But as a close analyst of technical market indicators, he is advising clients that by year-end the market is likely to rise, though with some caveats.

There may well be a correction — a relatively modest decline — in the next few months, his firm has concluded. But it is telling clients that a cyclical bull market is in place — a strong upturn within the longer downward trend.

This may well seem confusing. Mr. Davis said as much, reassuring clients: “I remain a secular bear. I am concerned about the long-term consequences of the Fed’s zero interest rate and easy credit policies and exploding government deficits.”

Despite these worries, he also said that it didn’t make sense, at least right now, to “fight the Fed and fight the tape.”

In a telephone conversation, Ed Clissold, United States market strategist for Ned Davis Research, explained the firm’s analysis, which has a wide following among money managers. Much of the apparent paradox is a question of timing, he said. “Four years from now, you may find that the stock market is trading in the same range as it is today,” he said. But, he added, it is likely to cycle up and down in the interim. And over a much longer time frame, “global deleveraging still needs to be completed, and that will have negative effects for the stock market.”

While the market may consolidate in the weeks ahead, two main factors argue in favor of a continuing upward trend this year, the firm has concluded. The first of these is “the Fed” — meaning the Federal Reserve and other central banks around the world, which have adopted extraordinarily accommodative monetary policies and committed to redoubling their efforts if economic growth falters. The stock market generally responds favorably to loose money.

The second is “the tape,” the momentum of the market and its individual sectors, which continue to show favorable patterns. In essence, what goes up tends to keep going up — until it no longer does.

And there are certainly many factors weighing on the market, both technical and economic.

A short-term consolidation might be in order after a stock market rise as sharp as the recent one; in a benign forecast, a modest decline would prepare the way for a bigger run upward for several months, which Ned Davis Research sees as the likeliest outcome. Stock valuations are already elevated, the firm says, and while that may not be an immediate problem, it implies that some excesses will need to be wrung out of the market down the road.

ENORMOUS problems remain for the global economy. The European financial crisis has been contained but not solved; further flare-ups are quite possible and could derail the market. Longer term, Mr. Clissold said, reversing the credit expansion and reducing debt loads are likely to have negative effects on riskier assets.

Buy-and-hold investors who maintain diversified portfolios and rigorously reinvest dividends and interest can try to ride out these cycles, Mr. Clissold said, and “have what will probably be modest returns” in the years ahead. Market professionals who try to do better than that will need to be nimble indeed.

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