© 2003 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 95, No. 12, 845,
June 18, 2003
© 2003 Oxford University Press
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First Proteasome Inhibitor Approved for Multiple Myeloma
Velcade (bortezomib), the first in a new class of investigational drugs known as proteasome inhibitors, was approved for use in multiple myeloma in record-making time—only 4 months after it had been submitted to the U.S. Food and Drug Administration.
"The drug shows a significant effect on patients with multiple myeloma that have not responded to other treatments—a response that is likely to result in significant clinical benefit," said FDA Commissioner Mark McClellan, M.D., Ph.D., in a statement about the May 13 approval.
By all accounts, Velcade, owned by Millennium Pharmaceuticals and co-developed by the Dana-Farber Cancer Institute, Boston, is an ideal drug to publicly expedite because of its novel action and apparent potential in the treatment of cancer. Use of Velcade in relapsed and refractory multiple myeloma, an incurable cancer of the bone marrow with an average survival of 3 years, demonstrated substantial response in patients whose cancer was progressing.
Approval of the drug was based on a 202-patient study at Dana-Farber in which 28% of patients had partial or complete responses with a median duration of about a year, and the disease stabilized another 18% of patients, said Dana-Farber investigator Ken Anderson, M.D.
Velcade’s efficacy is "remarkable," considering that patients tested had averaged "six prior lines of therapy," including one patient who received "two autologous transplants, thalidomide, steroids, and then an allogeneic transplant," Anderson said at a symposium at Harvard Medical School in May.
Not only is Velcade the first treatment in more than a decade to be approved for patients with multiple myeloma, it is the first proteasome inhibitor to receive FDA approval for the treatment of cancer, and that is what much of the bench-to-bedside buzz surrounding its approval is about, researchers say.
"Only about a decade elapsed from initial appreciation of the importance of the proteasome pathway to development of drugs and the carrying out of clinical trials, and that’s very exciting," said Anderson’s Dana-Farber colleague, pathologist Peter Howley, M.D.
Velcade is the first drug whose mechanism of action focuses on cellular proteasomes—the 30,000 or so "garbage disposal" molecular machines studded throughout the cell that chew up proteins tagged for destruction, either because they are misfolded or abnormal in some way, or because they are not needed anymore. The importance of the proteasome arose as researchers realized that cells are bags of thousands of proteins that are not static, but continually turning over, either being made or broken down at various rates, said Harvard Medical School cell biologist Alfred Goldberg, Ph.D.
Researchers now recognize that the proteasome "precisely regulates cell growth and metabolism" by maintaining the right balance of cellular proteins and that "many diseases are associated with either too much or too little degradation of proteins," said Goldberg, who conducted some of the early work on proteasome function.
For example, accelerated degradation of proteins by the proteasome contributes to cystic fibrosis, muscle wasting, and some cancers, whereas failure of this system underlies other cancers and neurological disorders such as Huntington’s and Parkinson’s diseases.
Proteasome inhibition represents a novel pathway for targeted anticancer therapy because cancer cells make more abnormal proteins and thus heavily depend on the proteasome to degrade them, said Julian Adams, Ph.D., Millennium’s senior vice president of drug discovery. Inhibiting activity of the proteasome in multiple myeloma blocks the transcription and secretion of cytokine factors that a cancer cell uses to grow and survive, and which also helps it resist standard chemotherapy and radiation treatment, he said.
Regulating proteasome activity in this manner has the potential to treat a number of cancers, Adams added.
The drug is now being tested in more than 40 ongoing clinical trials in a collaboration between Millennium and the National Cancer Institute, Adams said. Although "there is virtually no cancer we are not studying," he said, tumors that are receiving the most intense scrutiny by researchers interested in Velcade’s effect include colon, lung, breast, and prostate cancers.
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