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McGill grad, Forbes cover boy and chemical entrepreneur Julian Adams talks about the development of blockbuster drug Velcade
Julian Adams is a drug pioneer with a terrier's tenacity and an eye on the prize. Now chief scientific officer at Infinity Pharmaceuticals in Cambridge, Massachusetts, Adams delivered a lecture in the Chemistry Department's Entrepreneurship Series on April 1. Close to a decade of effort has seen his anti-cancer drug, Velcade, graced by the recognition of the Nobel Committee. Velcade pushes cancer cells into their death throes without harming normal cells, and it isn't subject to the resistance mechanisms most cancer drugs experience.
"People think of cancer as a disease in which cells just keep dividing. But only about one percent of cancer cells are actually proliferating. The thing is, they just refuse to die."
Adams obtained his BSc in chemistry at McGill in 1977. "I wanted to stay on and continue working with David Harpp, a terrific teacher," but Harpp and colleague George Just encouraged Adams to broaden his horizons. Going on to obtain a PhD at MIT and an NSERC postdoctoral fellowship at Columbia University, Adams had his heart set on academic chemistry. But he discovered few such positions available in Canada in the early '80s.
Instead, Adams became the youngest senior research chemist at Merck Frosst. Adams left Merck for BioMega, a division of German drug giant Boehringer Ingelheim; he headed the team that created Viramune, a drug grossing $370 million (US) annually. It was the first in a new class of HIV treatments: non-nucleoside reverse transcriptase inhibitors. Adams then founded ProScript, which later became Infinity.
The 2004 Nobel Prize for Chemistry was awarded to Aaron Ciechanover, Avram Hershko and Irwin Rose for discovering "ubiquitin-mediated protein degradation," including the groundbreaking finding that protein levels are controlled as much by their degradation as by their synthesis. The Nobel Committee mentioned Adams's latest success in reports of the award.
Velcade, also the first drug of its kind, knocks out functioning of the proteasome, the cell's protein garbage disposal. Proteins with errors in their makeup are tagged for destruction with the molecule ubiquitin, a cellular "kiss of death." They then shuttle to the cylindrical proteasome to be chopped up into short fragments of their component amino acids. One Saturday morning in Munich, Adams had a "eureka moment": he realized he could block proteasome function by substituting a critical aldehyde group with a boron atom, creating a molecule the proteasome could neither break apart easily nor let go of. There had never been a successful boron-containing medication before. Adams knew it was unorthodox (a German researcher stormed out of a seminar over it), but the chemistry was so clear to him that it was a risk he had to take.
He made his compound widely available to collaborators early on, quickly generating reams of data. "To survive, small biotech companies like mine needed to network like crazy. We couldn't be paranoid. As a result, in a very short time we had between 50 and 100 academic centres experimenting with our compound in cells and mice."
Adams estimated there are 450 cancer drugs in American clinical trials. Velcade was initially tested on "the sickest of the sick -- cancer patients facing the choice between palliative care or experimental treatment." The trial garnered impressive results: 45 percent of patients showed significant improvement, including 10 percent who went into remission.
The patients had multiple myeloma, a cancer of plasma cells that mature in bone marrow and make antibodies. Affected by this condition, plasma cells can't exit the bone marrow normally; they can't make proper antibodies, either. Patients come to medical attention with unexplained fractures or immune system abnormalities. Dysfunctional antibodies circulate in the blood and end up causing kidney damage. At diagnosis, patients had a three- to five-year projected survival.
"We only expected 10 percent of these patients to show any improvement at all. Ninety-one percent of them had gotten worse on their previous treatment." They had already been through many rounds of therapy. With Velcade, median survival doubled to 16 months. Objective measures also showed improvement in quality of life: rising hemoglobin levels improved kidney function, allowing many to stop dialysis treatment. In 2001, Adams was awarded the Ribbon of Hope Award from the International Myeloma Foundation.
The U.S. FDA fast-tracked the drug, issuing approval in 2003. He made the cover of Forbes, the issue titled "Drugs and Genius." Velcade is now the standard of care for multiple myeloma. Canada also recently approved Velcade, and Adams was in Montreal for the Canadian launch. Now being tested against other cancers, Velcade is creating a loud buzz.
After years of fine-tuning, treatment is designed to damp down proteasome functioning by 80 percent. "Experiments proved that cancer cells are 10 to 100 times more sensitive to proteasome inhibition than normal cells." That's because cancer cells have accumulated many mutations; in the best of times, they are riddled with malformed proteins that require disposal. If the proteasome is shut down even partially, mutant proteins overwhelm the cancer cell, triggering the cell's suicide program. By contrast, hobbling proteasome function in normal cells causes little damage because there are fewer proteins awaiting degradation.
For those in the molecular biology "zone," Velcade is an antiangiogenic, an inhibitor of NF-kB activation and a stabilizer of cell cycle regulatory proteins (in other words, it stops the cell in its tracks, no matter where it is in the cycle of growth and division).
"At McGill, I got great fundamentals, though one of my first experiments set the fume hood on fire."
To be successful, Adams told his audience, it is "important to know where the science is going and to do what you like to do." For Julian Adams, good foundations, a stimulating subject, hard work and the ability to keep an open mind have created a chemical equation for success.