The road to discovery
Over the past 25 or 30 years, scientists have shown that cancer is a disease caused by a combination of inherited tendencies and newly acquired mutations, or changes, in the genes that normally regulate cell growth, maturation, repair of DNA damage, and cell movement.
The new drugs are aimed at these damaged "oncogenes" with such precision that they ignore normal genes and cells. Scores of such drugs are in development, but many are years away from clinical use. The arrival of Gleevec and its dramatic success in CML and GIST has injected a new note of optimism that cancers might be controlled — perhaps for many years or a lifetime — with gentler drugs.
Dana-Farber physician-scientists (left to right) James Griffin, MD, Thomas Roberts, PhD, and Charles Stiles, PhD, contributed to Gleevec's discovery with fundamental work on chemical signals that turn normal cells into cancer cells. New "smart" drugs like Gleevec specifically attack these signals.
"We are succeeding more and more in our quest to turn cancer into a chronic disease that can be managed to give patients many years of high-quality life," says Demetri.
Gleevec showed such promise in early clinical trials against chronic myelogenous leukemia in 1999 that the Food and Drug Administration (FDA) "fast-tracked" its approval for widespread use. In May 2001, the FDA okayed Gleevec after only two-and-a-half months of reviews — fastest ever for a cancer drug.
The day after it was approved, Victor Rutana, a CML patient from Bridgton, Maine, stood in the DFCI office of Richard Stone, MD, as the physician wrote out what he believes may have been the first prescription for Gleevec outside a research trial. Rutana, whose blood counts from CML returned to normal after taking Gleevec, is saving that first prescription as a piece of medical history. Stone says Gleevec has worked in about 70 percent of CML patients who failed all other therapies, including interferon.
CML, which strikes about 5,000 people in the United States each year, is caused by an overactive growth signal in white blood cells that spurs them to proliferate wildly, damaging the bone marrow, liver, and spleen. This maverick growth signal is transmitted by mistake in white blood cells when two specific chromosomes are damaged, and the broken pieces swap places. Because of this mishap, the cells overproduce a protein called BCR-ABL, a type of enzyme known as a tyrosine kinase.
In the mid-1980s, Stiles and some of his colleagues at Dana-Farber were probing tyrosine kinases and other growth signals in hopes that blocking them might result in a more specific way to thwart cancer. Also plotting this strategy was the Swiss pharmaceutical company Ciba-Geigy Corp. (now Novartis Pharmaceuticals), which in 1985 launched a research effort to find compounds to inhibit tyrosine kinases. At that time, CML was the only cancer known to be caused by an overactive version of this enzyme.
Gleevec represents a new era of treatments known as "targeted" agents, aimed at newly discovered Achilles' heels in cancer cells.
In its quest for new cancer drugs to block such signals, Ciba-Geigy needed scientific help. Alex Matter, director of the company's research efforts, recruited DFCI's Stiles and Roberts, who made several trips to Switzerland to share their expertise. Among the findings Roberts relayed to the company were his method of producing oncoproteins — the chemicals produced by cancer-causing oncogenes — in the laboratory.
At the same time, a young physician-researcher in Roberts' lab was collaborating with him on work related to tyrosine kinases. He was Brian Druker, MD, who arrived at DFCI in 1984, and trained and did research here for nearly a decade. He became a driving force behind the concept of blocking BCR-ABL and in developing and testing Gleevec — even though the drug company initially lacked interest. In the late 1980s, Druker and Roberts devised an important laboratory test for tyrosine kinase activity that helped in finding drugs to block it.
Druker wanted to take what he was learning in the laboratory and apply it to improving the lives of cancer patients. "My background was in human diseases," he says, recalling his surprise during training at how sick chemotherapy made patients, even when it worked. Gleevec is free of severe side effects.
Seeking a research project, Druker sought advice from James Griffin, MD, a Dana-Farber specialist in blood cancers. "I suggested he work on CML, which was the one human disease we knew was caused by a tyrosine kinase," Griffin recalls.
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