HARVARD GAZETTE ARCHIVES

Alfred Goldberg explains the structure of a protein shedder that is present in all cells. He and his colleagues have discovered how to drug the device so that it will shrink tumors in an often fatal cancer. (Staff photo by Kris Snibbe)

At the beginning of Goldberg's quest 35 years ago, very little was known about the destruction of proteins in our cells. Until recently, most biologists focused their interest on how proteins are made using the DNA blueprints encoded in genes. They ignored the mystery of why the body continuously destroys its imperative ingredients.

By the mid-1990s, Goldberg and his colleagues had worked out the structure and the purpose of one of the most magnificent molecular machines put together by nature. It acts like a garbage disposal in creatures ranging from bacteria to medical students, chewing up abnormal and damaged proteins that otherwise clog up the operation of a living cell. It also destroys key proteins that regulate growth and metabolism, and by this mean it terminates processes when they are no longer needed, or activates others that allow cells to adapt to new conditions.

A disease-munching machine

Goldberg christened this natural shedder "proteasome," or a particle that cuts proteins. The shedding is so important to life that an average cell, say a red blood cell, has 30,000 proteasomes. You can imagine how difficult it was to determine the structure of something that small and to figure out how it can selectively rip up abnormal proteins without damaging those that are essential for normal cell survival.

Such a machine should be valuable for treating diseases like muscle wasting and other maladies that involve protein destruction. Goldberg reasoned that making a drug that slowed the chewing up of normal proteins could put a brake on such sickening activities. He and his team tried to sell drug companies on the possibilities, but the industry declined to get involved. The whole idea was just too radical. Most experts feared that slowing down or blocking cellular garbage disposal might prove toxin to normal cells.

Goldberg decided to pursue this idea with the help of three other Harvard Medical School professors, Thomas Maniatis, Michael Rosenblatt, and Kenneth Rock (now at the University of Massachusetts Medical School). They started their own biotechnology company and hired a team of chemists, biologists, and physicians to develop drugs to selectively brake proteasome activity.

Their experiments suggested such drugs might be useful for treating cancer. Follow-up studies showed that the compounds shrunk human tumors growing in mice.

Then their company ran out of money. But things looked promising enough for Goldberg's company to be bought by another company, which in turn was bought by Millennium Pharmaceuticals of Cambridge, Mass. By 1999, a new drug, now called Velcade (bortezomib), was approved for trials with cancer patients.

Much to everyone's delight, the drug shrank a number of different types of tumors. But the most exciting results came from patients with multiple myeloma, an often fatal cancer of white blood cells that destroys bone marrow.

"Velcade helped seven out of the first 10 patients in our trials, one of whom showed complete remission," notes Julian Adams, a senior vice president at Millennium. About 50,000 people in this country suffer from multiple myeloma, and it kills 12,000 of them a year. "We treat them with several drugs, blood transfusions, and bone marrow transplants that work for a while, but the disease is incurable," notes Ken Anderson, Kraft Family Professor of Medicine, who directed the human trials "New cases appear at the rate of 15,000 a year."

In 2000, the researchers gave the new drug to 202 multiple myeloma patients who faced death because they did not respond to other treatments. Velcade helped 119 of them, shrinking their tumors or reducing their need for blood transfusions. Several seemed to be completely cured.

"No cells can live without proteasomes," Goldberg notes, "but Velcade is given at doses that only partially block the function of these machines. Normal cells survive such doses, but cancer cells die."

Just the beginning

Attacks on normal cells are what cause the debilitating side effects of most cancer drugs, but the dramatic improvement in multiple myeloma patients occurred without the patients suffering much toxicity. Millennium felt confident enough about the outcome to petition the Food and Drug Administration for accelerated approval of the drug for widespread use without the further testing that the agency usually requires. On May 13, FDA granted that request.

In the event that approval would not be given, Millennium began further tests of the drug last year. Three hundred people at 80 different hospitals are taking Velcade, and their progress will be compared with a like number of patients who don't take it.

And that's just the beginning. "The biggest opportunities lie ahead," Goldberg maintains. He refers to the potential of using Velcade to treat the really big killers - - lung, prostate, breast, and colon cancers. Millennium has more than 40 trials ongoing to test the drug on these and other types of cancer. "Trials with animals indicate that Velcade is most effective against major cancers when it's used in combination with other drugs or radiation, that are now part of the standard treatment," Goldberg adds.

Millennium and other companies are developing different proteasome drugs that may prove useful for treating a variety of other diseases. For example, a proteasome blocker is now being tested on humans to treat strokes.

"It's gratifying to find our discoveries both printed as facts in new textbooks and used as knowledge that benefit patients with terrible diseases," Goldberg says. "The lesson for young scientists is that, if you work on truly fundamental questions, a wide range if exciting intellectual implications and practical applications can result, even in areas you would never predict."