Accident led to cancer treatment for 'Philadelphia chromosome'

Codiscoverers of the Philadelphia chromosome Peter Nowell (left) and David Hungerford in 1962, in photo from Hungerford's widow, Alice.
Codiscoverers of the Philadelphia chromosome Peter Nowell (left) and David Hungerford in 1962, in photo from Hungerford's widow, Alice.
Posted: September 29, 2010

In 2005, Ryan Corbi was a senior at Villanova, pondering whether to pursue a career in medicine or theology when his doctor told him she suspected he had leukemia.

He felt fine, but some routine blood work looked suspicious. He soon found himself at Fox Chase Cancer Center, where doctors took a sample of his bone marrow and tested it for something he'd never heard of at the time - the Philadelphia chromosome.

Now he's intimately familiar with this bit of errant genetic material that triggers his particular form of the disease - chronic myeloid leukemia (CML). Tuesday, at a symposium devoted to the 50th anniversary of the discovery of the Philadelphia chromosome, the tall, healthy-looking 27-year-old said he owed his life to a decades-long scientific odyssey that began here in 1958.

It started with a mistake. University of Pennsylvania pathologist Peter Nowell accidentally used tap water rather than a special solution to rinse some slides coated with leukemia cells.

Nowell could have thrown the slides away, but he saw something curious and decided to look further, teaming up with a Fox Chase graduate student. That led to a 1960 paper that changed the direction of cancer research and led decades later to a drug that Corbi credits with his survival.

Corbi said that once the doctors found the Philadelphia chromosome in some of his cells, they told him it was good news and bad news. Unfortunately, he had leukemia, but it could be treated with a new drug, part of a new class that selectively disables cancer cells while sparing normal ones.

At the symposium, held all day Tuesday at the Chemical Heritage Foundation in Center City, Corbi said he had never felt a single side effect - never lost his hair or had to worry about his fertility. The only thing that has changed is he takes one pill a day.

At first, he said, doctors were unsure if he should have a bone-marrow transplant and undergo chemotherapy before getting the new drug. But he and his doctors opted to skip the traditional treatments.

He has earned a master's degree in theology and is hoping to teach.

Former Los Angeles Lakers basketball star Kareem Abdul-Jabbar also has the Philadelphia chromosome. Although he could not be at the symposium, he sent a letter expressing his gratitude toward all the researchers whose devotion led to the drug that is keeping him healthy despite having CML.

Nowell, 82, told the crowd of several hundred that washing his slides in tap water caused the chromosomes in the cells to swell and take shape. Most of the time, chromosomes spread out and overlap, like spaghetti.

Nowell said he didn't know much about chromosomes - it was only two years earlier that biologists had figured out that humans have 46 of them. But it seemed a shame to throw these slides away, he said. Something might be learned from them.

"Someone mentioned there was this fellow named David Hungerford over at Fox Chase Cancer Center who was trying to do a Ph.D. in chromosomes," Nowell said.

The two teamed up, and Hungerford noticed that the leukemia cells carried an extra chromosome - a tiny, stunted-looking one.

Hungerford's observation was even more impressive considering the state of equipment he used, said Jeff Boyd, executive director of Fox Chase's Institute of Personalized Medicine. "He made a seminal discovery using a microscope you could probably buy at Toys R Us today."

Nowell and Hungerford studied more cells until they had made a case that this stunted chromosome was associated with malignant cells in patients diagnosed with CML.

They published their findings in 1960, when it was traditional for such findings to take on the name of the city where they were discovered.

"It was a decisive moment," said Fox Chase cancer researcher Alfred Knudson, 88, who attended the symposium. He said the finding had a powerful influence on the direction he took in his career.

Back in 1960, some thought cancer might be caused by radiation. Others thought it was viral, Knudson said. Nowell and Hungerford showed that in one type of cancer, at least, a genetic abnormality cropped up in the malignant cells.

Knudson went on to show how inherited genetic mutations could conspire with subsequent DNA damage to cause cancer.

That helped lay the foundation for the modern understanding that all cancers are at the root driven by genetic changes. In some cases, growth-inhibiting genes called tumor suppressor genes are damaged, allowing cells to proliferate unchecked.

Other times, growth-spurring genes called oncogenes could be activated in the wrong place at the wrong time.

That's what was going on in CML patients, but it took decades before scientists figured that out.

In the 1970s, biologist Janet Rawley of the University of Chicago figured out that the Philadelphia chromosome was made up of a fragment of Chromosome 22 that had broken off and become stuck to a fragment of Chromosome 9.

Speaking at the symposium, Rawley, 85, explained how she came to figure this out and later connect this abnormal hybrid chromosome to CML.

In the 1980s, other scientists figured out how the Philadelphia chromosome could cause cancer. First, they identified a gene called abl that had been associated with other cancers. In normal cells, this so-called oncogene is located on Chromosome 22, where it stays quiet. But in the Philadelphia chromosome, it acquires a new neighbor, a gene called bcr that comes from the fragment of Chromosome 9.

The bcr activates the abl gene, and the combination spurs uncontrolled malignant cell growth.

It all starts with just one cell, since the abnormal pairing of genes prompts that cell to copy itself thousands of times over.

While CML often starts off slowly, it can reach a crisis phase. In some cases, patients' blood becomes so thick that it can't circulate properly through vital organs. The disease was often fatal within a few years of diagnosis.

By the 1990s, drug-discovery technology had advanced and researchers began searching for a molecule that would stop the action of this deadly duo of misplaced genes.

They found a good candidate and started testing it on CML patients in 1998.

In 2001, the Food and Drug Administration approved the drug, Imatinib, which goes under several brand names including Gleevec. It was one of the fastest actions on a new drug in the agency's history.

Meanwhile, another Fox Chase oncologist, Margaret Von Mehren, tested the drug on patients with a cancer called gastrointestinal stromal tumor (GIST). The GIST cells had no Philadelphia chromosome, but they did have a similar growth-promoting protein.

Many of the GIST patients recovered.

The scientists hope all their inquiry into the molecular mechanisms of cancer will lead to more such "targeted therapies" - ones that don't lead to the nausea, hair loss, and other toxic side effects of chemotherapy and radiation.

So far, there is one other example - a drug called Herceptin, which works on breast cancer cells with a particular genetic profile.

Imatinib is not a cure. Corbi still has leukemia cells lurking in his body that would probably return if he stopped taking the drug.

The long-term effectiveness has yet to be proven. The very first patients have been taking it for only about a decade. At 27, Corbi is counting on it working for much longer.


Contact staff writer Faye Flam at 215-854-4977 or fflam@phillynews.com.

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