If luck favors the prepared, it also smiles upon the passionate and the persistent.
Julian Adams, Kenneth Anderson Alfred Goldberg and Paul Richardson, the winners of the 2012 Warren Alpert Foundation Prize, certainly fit the description of all three as they shared the inside story of their discovery and development of the drug bortezomib at the foundation's award ceremony Sept. 24. The drug, also known by the trade name Velcade, has prolonged and improved the lives of hundreds of thousands of people with the deadly blood cancer multiple myeloma, and opened new avenues of medical and basic biological research.
Its discovery is a story of serendipity and of stubborn dedication, of remarkable independent insights, and the broad, deep collaborations that are at the heart of all modern biomedical breakthroughs.
“It is a story we too rarely get to tell, of how curiosity-driven science, through a series of steps over many decades, evolved into an innovative therapy that has changed the lives of many patients,” said Jeffrey S. Flier, dean of Harvard Medical School and chair of the Alpert Prize selection committee that chose the winners.
Speaking at the 2012 Warren Alpert Foundation Prize Symposium, Flier introduced the winners as they presented the history of the development of bortezomib.
Basic scientific research is crucial for medical advancement
The tale began in 1966, when Alfred Golberg, now HMS professor of cell biology, was a first year medical student at HMS. Driven by pure curiosity about the underlying causes of muscle wasting in disease, he performed a simple experiment that provided surprising results: even as they shrank, disused muscles continued to synthesize proteins at the same rate as muscles that were still in use and maintaining their size. He realized that some then-unknown process must be at work breaking down and withering away the proteins in idle muscles.
(HMS has launched its Scholars in Medicine program designed to inspire just this kind of curiosity and knowledge creation among first year medical students.)
Goldberg continued his research, eventually discovering the proteasome, a fundamental piece of molecular machinery that is responsible for removing damaged and pathogenic proteins from the cell and for recycling proteins and their constituent amino acids for re-use in the cell.
In 1993, Goldberg teamed up with three other investigators to establish a company with the primary goal of inhibiting the proteasome in order to treat muscle-wasting conditions. They developed chemicals that could completely block protease activity.
“Once you block the proteasome, the cell looks like a city in a garbage strike,” Goldberg said. The team wondered if their techniques might have therapeutic uses for treating diseases that had processes that relied on heavy use of the proteasome. Julian Adams, a medicinal chemist was recruited to the start-up team and the work began to see what potential therapeutics might be developed, with a new focus on cancers.
Collaboration in medical research
Adams, now president of research and development at Infinity Pharmaceuticals, oversaw the relentless pursuit of this molecule, through the start-up phase of the company and multiple acquisitions by larger firms, through challenging clinical trials to ultimate FDA approval.
The journey was not always smooth. Collaborations with the National Cancer Institute showed that inhibiting the proteasome has a remarkable capacity for eliminating certain types of cancer cells, but at slightly higher dosages, bortezomib can be extremely toxic to healthy cells.
In the course of unsuccessfully pitching potential collaborations to 56 pharmaceutical companies, Adams said, he met strong resistance. The drug’s unusual chemistry included a boron molecule, which was unheard of at the time, causing some to question the applicability of the drug. One of the team’s own scientific advisors told Adams, “Only a moron would put a boron in a drug,” but this turned out to be a very effective approach.
One tumor type that proved especially vulnerable to Velcade was multiple myeloma, so the team began to work with Kenneth Anderson, HMS Kraft Family Professor of Medicine at Brigham and Women's Hospital and the Dana-Farber Cancer Institute, one of the world’s leading experts on multiple myeloma.
Anderson said that the new field of protease inhibitor research has not only opened new avenues for potential treatment, but has also opened new avenues for understanding the fundamental biological processes that underlie healthy and cancerous cells, which, in turn, have created still more new avenues for potential treatments.
“This research has taken us from bench to bedside and back to the bench with investigators from all over the world,” Anderson said.
He particularly emphasized the importance of understanding how these processes work in the particular microenvironment where cancer exists. This systems approach helped researchers understand the application of bortezomib as a powerful partner for other drugs in combination therapy leading to better outcomes.
Even when Velcade moved into clinical trials, the team continued to build partnerships with basic science researchers, as they worked to understand the causes and potential treatment for some of the side effects of the drug. “We are truly two hands clapping, the laboratory and the clinic,” said Paul Richardson, leader of the clinical trials and associate professor of medicine at Brigham and Women's Hospital and the Dana-Farber Cancer Institute also a world-class expert on the disease. The clinical trials proceeded at record-breaking pace, and in 2003 the FDA approved the drug for clinical use.
The last featured speaker was neither a clinician nor a scientist, but an artist. Charlie Movalli, who was a subject in the first round of clinical trials, talked about how his struggles with multiple myeloma and its complications have encouraged him to follow his own passions as a painter. He was struck, he said, by the researchers’ curiosity and passion —not simply for funding a cure, but for the pursuit of understanding. “The love of doing something for its own sake, that is the spirit of artist,” he said.
“I was not aware until recently how important the drug was,” Movalli said. “I’m impressed now at my own contribution to medical science. And I can thank this team for keeping me alive so I can actually enjoy it.”
The researchers will share an unrestricted prize of $250,000. The Alpert Prize, now in its 25th year, recognizes researchers for biomedical research discoveries with dramatic promise to improve human health.