The Birth of a Targeted Therapy
A decade later Rowley was vindicated, after geneticists showed that chromosome 22’s missing piece joined up with chromosome 9 in the neighborhood of a cancer-related gene. The new hybrid gene began making a protein that acts like a molecular “on” switch that causes cells to replicate out of control. This newly discovered biochemical pathway was later named BCR-ABL, after the particular genes—BCR and ABL—located at the breakpoints of the two chromosomes.
The 9;22 translocation is a glitch, an accidental mutation that occurs when the stem cells in the bone marrow divide. The mutation initially occurs in just one white cell, but each time that cell and its offspring divide, they pass on the translocation. The fused gene makes a product that tells cells to replicate continuously, causing leukemia.
It wasn’t good news, as Nowell would put it, but it was better news. Researchers now had a clear target to aim for: If they could interrupt the BCR-ABL pathway—the product of the translocation—the leukemia should shut down.
A Critical Collaboration
The lure of CML—a cancer caused in a clearly defined way, by a specific protein that’s produced consistently by a known genetic abnormality—was irresistible to Druker when he entered the research field. During medical school, he had become convinced that the best way to fight cancer was at the molecular level. “I wouldn’t exactly say I was obsessed with the idea,” says Druker. “But I couldn’t think of any reason why it wouldn’t work.” So in the early 1990s, intent on developing a targeted cancer therapy, he decided to take up the gauntlet.
As an oncologist at the Dana-Farber Cancer Institute in Boston in the late 1980s, Druker had seen his share of CML patients. And he knew firsthand how little there was to offer them. Druker may not have been able to think of any reason why targeting the BCR-ABL pathway wouldn’t work, but his superiors believed the idea wouldn’t amount to much. Undeterred, Druker moved across the country in 1993 and set up shop in Oregon.
He also began collaborating with Alex Matter and Nicholas Lydon, like-minded biochemists at the drug company that would eventually become Novartis. Lydon had become proficient in a high-tech method of pharmaceutical testing called “high-throughput screening” that enables thousands of chemical compounds to be quickly tested for potential activity against a particular biochemical pathway. Using this method, Lydon’s lab would find compounds that had potential activity against the BCR-ABL pathway and send them to Druker for testing. Eventually, they hit on a winner—a molecule that killed every leukemia cell in Druker’s petri dishes. But just when it looked like the researchers were on to something, Lydon’s company underwent a merger and Lydon left. Without Lydon’s advocacy, the executives weren’t convinced that Druker’s new drug was worth the substantial investment of clinical trials. After all, there wasn’t a lot of profit potential in a drug for a disease that’s diagnosed in only about 5,000 Americans a year.
Druker rallied colleagues at OHSU and other institutions for support. Ultimately, he found an advocate in Matter, who had stayed with the company and who went on to champion the drug through further trials. “At one point, I even thought about passing around a petition,” says Druker. “In 1996, I had a patient who was a dot-commer. … His leukemia was poorly controlled, and I remember at one point, he said, ‘Can’t you just go upstairs to the lab and get me some of that drug you’re working on?’ He later died. That sort of thing is really motivating. I’m not sure that if I had been just a researcher, I would have had the same level of commitment.
Druker’s dedication paid off. Phase I clinical trials are typically considered very successful if 10 to 20 percent of the participants show a significant positive response to the drug being tested. The first imatinib trial had almost a 100 percent response rate, with nearly all of the 54 patients seeing Lazarus-like responses like Jenson’s. “I remember thinking that it was almost too good to be true,” says Druker.
In fact, it was better. Less than three years after Jenson enrolled in Druker’s phase I trial, Gleevec was giving new hope to CML patients—as Corbi’s more encouraging experience with CML shows. And while, over time, about 20 percent of patients develop some resistance to Gleevec, Druker and others have found similar drugs that work when Gleevec no longer does. (See "What Happens When a Miracle Drug Doesn't Work Miracles?") Moreover, Gleevec isn’t effective in only CML. It has been approved for gastrointestinal stromal tumors (GIST), certain skin cancers and other types of leukemia.
“What was really important about Gleevec was that it paved the way for other drugs to target molecular events in cancer,” says Jeff Boyd, the executive director of the Cancer Genome Institute at Fox Chase Cancer Center. “There are 30 targeted therapies now FDA-approved, and they all go back to Gleevec.”
That number is expected to grow as technological advances in high-throughput drug screening and cancer genome screening and analysis get cheaper and faster, says Charles Sawyers, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City who helped develop Gleevec, and who has also helped develop a targeted therapy for prostate cancer called MDV3100 that is now in phase III clinical trials. “It’s only been in the past few years that we’ve really seen the technology take off—there are a lot of really promising drugs in the works.”
Corbi is fine with the idea of being on Gleevec for the rest of his life. But he doesn’t think he will have to be. “If you think about how far this whole process has come in 50 years and especially the last 10 years, I’m pretty sure that something that knocks it out completely will come along in my lifetime,” says Corbi.
“I have a lot of faith in that.”
JOCELYN SELIM is a veterinary student and freelance science and health writer in Gonzales, La.