Professor Avraham Hershko (left) and Dr. Aaron Ciechanover led the Technion team that discovered the system that degrades proteins – the ubiquitin system. The U.S. Food and Drug Administration has approved a new drug to fight cancer, which is the result of 30 years of research by Israeli scientists.
Velcade, developed by Millennium Pharmaceuticals of Cambridge, Massachusetts, is the result of work headed by Prof. Avram Hershko of the Technion-Israel Institute of Technology in Haifa on ubiquitin – a small protein involved in protein degradation.
Velcade “shows a significant effect on patients with multiple myeloma that have not responded to other treatments,” said FDA Commissioner Dr. Mark McClellan. Velcade was in the FDA’s accelerated approval program that speeds up approval of promising drugs for life-threatening diseases.
Multiple myeloma is the second most prevalent blood cancer after non-Hodgkin’s lymphoma, according to the FDA. Some 45,000 people in the U.S. alone have multiple myeloma, and an estimated 14,600 new cases are diagnosed each year.
Velcade is the first in a new class of anti-cancer agents known as proteasome inhibitors. Five years after he began researching the subject, Hershko and his Technion team, including former student Dr. Aaron Ciechanover, discovered the system that degrades proteins – the ubiquitin system.
“It uses a small protein called ubiquitin to mark the proteins that have to be degraded at the right time and the right place in the cell,” Hershko told The Jerusalem Post. “If proteins are not degraded at the right time, the cell continues to divide unchecked. This is what happens in many cancer cells; something has gone wrong in the ubiquitin system so there is no control over cell division.”
“The FDA approval of Velcade represents a major advance in our fight against multiple myeloma,” said Ken Anderson, M.D., director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, Mass. and the lead investigator in the preclinical development and clinical trials of Velcade. “With its new and unique mechanism of action of inhibiting the proteasome, Velcade is different from traditional chemotherapies and represents a new treatment option for patients.”
Velcade is just the “first drug to be developed based on this basic research done in my lab,” said Hershko, who is also an Israel Prize laureate. “I am sure that many other new drugs will be discovered which are targeted against specific things that go wrong in the ubiquitin system in different types of cancer. These include cancer of the colon, breast, prostate and melanomas.” Hershko’s research was partially supported by the Israel Cancer Research Fund.
Hershko and Ciechanover have received numerous awards for their pioneering medical research, including the Wolf Prize in Israel and the Lasker Award for Basic Medical Research (considered a precursor to the Nobel Prize).
More than 20 years ago, Hershko and Ciechanover became intrigued by the way in which proteins are degraded. Through rigorous biochemical experimentation, the researchers showed how ubiquitin – a small protein named for its ubiquitous distribution in nature – is attached to other proteins, thus marking them for destruction.
“Many people knew how the body produces proteins, but not how they were destroyed,” Hershko said. “Without an engine, a car cannot run; without brakes, it runs without control. Proteins provide ways to moderate the body’s machinery.”
The ubiquitin system has become central to the understanding of the emergence and progression of cancer, as well as other diseases. In the Lasker Award Jury citation in 1999, Chairman Dr. Joseph Goldstein, the Nobel Prize Laureate in Medicine and Physiology, notes the significance of the researchers’ work. He lauded their discovery and recognition of the significance of the ubiquitin system of regulated protein degradation, which he termed a “fundamental process that influences vital cellular events, including the cell cycle, malignant transformation, and responses to inflammation and immunity.”
Upon receiving the Lasker award, Hershko expressed gratification that his work is having a strong impact on cancer research. “I don’t think we will find a cure for all kinds of cancer, but I hope that through what we have done, some cure will be found for certain types,” he said. “I am especially hopeful for cancers such as colon cancer, cervix cancer and melonomas, as well as some other cancers known to be commonly caused by abnormalities in protein degradation.”
According to the Millenium Pharmaceuticals, Velcade and proteasome inhibition represent a completely new approach to treating multiple myeloma. The development of this product is based on the company’s deep understanding of cancer disease pathways and the effect of proteasome inhibition on those pathways. The proteasome is an enzyme complex that exists in all cells and plays an important role in degrading proteins that control the cell cycle and cellular processes. By blocking the proteasome, Velcade disrupts numerous biologic pathways, including those related to the growth and survival of cancer cells.
“Today, the thousands of people living with multiple myeloma in the United States have been given a new treatment option,” said Kathy Giusti, president, Multiple Myeloma Research Foundation (MMRF), and a myeloma patient. “The MMRF has been committed to helping accelerate the search for a cure for multiple myeloma and we are proud to have been able to work with Millennium in bringing this important new therapy to patients.”
“Velcade is the kind of cutting-edge treatment for which we have been advocating, and provides a new treatment option for the thousands of patients with this disease,” said Susie Novis, president, International Myeloma Foundation (IMF). “The approval of Velcade represents a major milestone in our quest to see new treatments made available to patients with multiple myeloma.”