Skip Ribbon Commands
Skip to main content

The Birth of a Targeted Therapy

A serendiptious discovery more than 50 years ago heralded a new age of cancer treatment. By Jocelyn Selim


In late 1998, Douglas Jenson was dying. Diagnosed with chronic myelogenous leukemia (CML) only a few months earlier, the 65-year-old Oregon native was already out of options. The drug he was on, interferon, didn’t work and was making Jenson sicker. Younger patients could opt for a bone marrow transplant—a high dose of chemotherapy or radiation to kill the cancer cells, followed by an infusion of healthy blood stem cells. But because of his age, Jenson was told he had less than a 10 percent chance of surviving the transplant, even with a perfect marrow match. So when his doctor told him about a researcher who was starting a phase I trial of a new drug, called STI571, he didn’t take too much time deciding whether to participate. After all, doing anything was better than just lying there in his hospital bed, waiting to die.

What Happens When a Miracle Drug
Doesn't Work Miracles?
Newer drugs are available
when Gleevec doesn't work.

Timeline of the Birth of a Targeted Therapy
From the double helix to Gleevec.

Within weeks, Jenson walked out of the hospital. Such miraculous recoveries are almost unheard of in the world of cancer treatments, especially in clinical trials. Then again, not every drug has the same backstory as STI571, now known as Gleevec (imatinib). “I had been told I had two or three years to live,” says Jenson, now 78. “One day I’m putting my affairs in order, the next I’m completely fine. That was more than 12 years ago. I take 400 milligrams of imatinib a day with breakfast. Actually, my knees bother me more than my leukemia.”

In 2005, Ryan Corbi’s experience was less dramatic but no less miraculous. Then a senior Villanova University near Philadelphia, Corbi went to see his doctor after he began experiencing stomach pain. Blood tests revealed his white blood cell count was sky-high. Within days, Corbi learned that, like Jenson, he too had CML. But unlike Jenson, Corbi was told he had a “good” cancer that could be treated with Gleevec. “I take a pill every day, and will probably have to for the rest of my life,” says Corbi. “To be honest, it’s not like having cancer or even a chronic disease, it’s like not having anything. I mean, I live a completely normal life.”

 

The New Standard of Care
In May of 2001, less than three years after the beginning of the first clinical study and in near record time, the U.S. Food and Drug Administration (FDA) approved Gleevec. It became the standard of care for CML almost the instant it appeared on the market.

Gleevec works by specifically targeting diseased cells. That’s why it doesn’t cause the often excruciating side effects that can occur with radiation and chemotherapy, which indiscriminately kill all
dividing cells, both healthy and cancerous. More important, Gleevec was proof-of-concept that understanding and specifically targeting subtle molecular changes that turn cells cancerous can produce more effective, less toxic treatments, and it has reshaped the cancer research field.

MAY 2001 
Less than three years after the beginning of the first clinical study and in near record time, the U.S. Food and Drug Administration approves Gleevec.

“There are hundreds of molecularly targeted drugs in the pharmaceutical pipelines, and that number is growing,” says Brian Druker, the medical oncologist at Oregon Health and Science University (OHSU) in Portland who led the team that developed Gleevec. Already dozens of carefully designed targeted therapies—like Erbitux (cetuximab) for colon cancer, Sutent (sunitinib) for some kidney cancers, and Tykerb (lapatinib) for breast cancer—have joined Gleevec as standard treatments.


A Serendipitous Discovery
All of these drugs, in some sense, originate from a serendipitous observation that the pathologist Peter Nowell made more than 50 years ago. Nowell had just taken a position at the University of Pennsylvania in Philadelphia after finishing up a two-year stint in the Navy, where he studied leukemia cells. “The university just let me do whatever I wanted to do,” says Nowell, “so I just carried on messing around with leukemia cells.” His research required that he wash the cells with tap water before staining them, which happened to make the cells swell up and the chromosomes easier to see. Nowell wasn’t a geneticist, but even he could see that there was an abnormally small chromosome present in some of the cells.

At the time, genetic studies were still crude— 
it was, after all, less than a decade since James Watson and Francis Crick famously elucidated the structure of the DNA double helix. And it was only a few years earlier, in 1956, that geneticists in Sweden had published a study that decisively proved that humans had 46 chromosomes (it had been assumed to be 48 since the 1920s). Once scientists knew what was normal, it was easier to identify what was not, making it possible to link chromosomal abnormalities to disease. In 1959, a Paris biologist linked Down syndrome to an extra copy of the 21st chromosome. By the early ’60s, extra or missing chromosomes were linked to other life-threatening birth defects and a constellation of lesser-known genetic disorders like Turner syndrome and Klinefelter syndrome.


High-throughput screening enables thousands of chemical compounds to be quickly tested for potential activity against a biochemical pathway.

Intrigued by what he had found, Nowell recruited a graduate student, David Hungerford, from Philadelphia’s Fox Chase Cancer Center and the pair began taking a closer look at blood samples taken from leukemia patients. The two quickly noticed that every single case of CML had the same abnormally tiny chromosome. When Nowell and Hungerford wrote up their discovery for publication in a 1960 issue of the journal Science, most of their colleagues regarded it as a curiosity. “I remember one of the reviewers telling me he thought it was interesting but that it had no scientific significance,” says Nowell. “They published it anyway, though."

Nowell and Hungerford didn’t know it, but they had identified the first-ever genetic signature for a cancer. They did know, though, that their finding strongly hinted that the mutation was the cause, rather than the result, of the leukemia. “That was good news and bad news,” says Nowell. “The good news is that we could suspect what the problem was; the bad news is, we didn’t have the technology to do anything about it at the time.”

Before long, another team of researchers dubbed the tiny chromosome, a dwarfed version of chromosome 22, the Philadelphia chromosome.


An Intriguing Observation
Nowell and Hungerford soon turned their attention to other areas, and the chromosome remained a mystery until it piqued the curiosity of Janet Rowley, a researcher and physician who was working part-time while raising four sons. She had become intrigued by genetics when she had worked with Down syndrome children, and she continued to follow the research. In 1972, sitting at her dining room table, Rowley was looking at pictures of chromosomes from CML patients who had been treated by a former professor. She noticed something odd about the Philadelphia chromosome: It was broken. It was small because a piece of it was missing. Even odder, Rowley found that the missing piece was glued on to chromosome 9.

100s          
"There are hundreds of molecularly targeted drugs in the pharmaceutical pipelines and that number is growing."

Rowley knew it was unlikely that finding a piece of chromosome 22 attached to chromosome 9 (called a 9;22 translocation) was simply a random by-product of the cancer. A random mutation wouldn’t be that consistently present in CML patients and absent in non-CML patients. Rowley believed she had found a smoking gun, and that it was the mutation that caused CML and not, as 
others had postulated, that the cancer had caused the mutation. She spent the next few years fervently arguing her case in scientific publications and at scientific meetings—but her colleagues paid little heed.


12/05/2011
SUBSCRIBE TO OUR E-NEWSLETTER

Receive monthly updates, including information about web exclusives, events, resources, articles and highlights from new issues—direct to your email inbox. Be among the first to hear the latest news from Cancer Today! Click here to sign up!