Oct 8

Oct 8 Fusion genes and cancer cures: The story of the Philadelphia Chromosome

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It’s 1960, and two young scientists – Peter Nowell and David Hungerford – have published a brief paper in the journal Science. It’s just 300 words long, but it’s about to set off a cascade of research that will change the way we think about cancer and medicine.

The paper compared the chromosomes of white blood cells from four patients with a type of leukaemia called chronic myeloid leukaemia (CML), with white blood cells from three healthy people. CML is a type of cancer that causes the white blood cells to multiply uncontrollably, eventually overwhelming the body. In the 1960s, there were no effective treatments, so a CML diagnosis was a virtual death sentence, with few patients surviving for more than five years.

Nowell’s and Hungerford’s work showed that in the cancerous white blood cells of people with CML, one of the chromosomes was usually short - a mutation that would become known as the Philadelphia chromosome after the city where Hungerford was working when he first spotted it.

Although scientists had uncovered the double helical structure of the DNA molecule seven years earlier, they had only just begun studying the structure and function of chromosomes - the long strings of DNA inside all our cells.

It wasn’t until 1955 that we even knew exactly how many chromosomes human beings have - check out episode 12 Strands of Life from our first series if you want more on that story. So in 1960, when Nowell and Hungerford’s research was published, genetic research into cancer and chromosomes was still in its infancy.

Like many great moments in science, Nowell and Hungerford stumbled into their revelation about the genetic origins of CML almost by accident.

In the 1950s, Nowell was a cancer researcher at the University of Pennsylvania, looking at the cancerous cells of patients with leukaemia in his laboratory. He hoped that studying the growth characteristics of cancer cells might give him some clues into how the disease developed.

Nowell was looking at human leukaemia cells that he’d grown in the lab on small glass slides, which he would carefully preserve and stain to reveal their chromosomes. One day he was feeling lazy (I’m sure we’ve all been there!), so he just rinsed them under the tap before staining.

The water caused the cells, which were mid-division, to swell up. In these swollen cells, the chromosomes spread out and became much easier to see. Nowell didn’t know much about genetics himself so he couldn’t interpret what he was seeing, but he suspected that his accidental discovery might be useful.

Drawing a blank in his own institution, he asked around the cancer research community, seeking a partner with knowledge of what chromosomes should look like who might be interested in this new technique.

It wasn’t long before he found David Hungerford – a PhD candidate and keen photographer working at the Fox Chase Cancer Research Centre in Philadelphia, who had spent years examining chromosomes under his microscope.

The pair soon started collaborating, perfecting the solutions and techniques that made the chromosomes in cancerous and healthy blood cells fan out like a peacock’s tail. Nowell sent over preparations of cancer cells splatted out onto slides, and Hungerford’s finely trained eye searched for abnormalities.

For years they found nothing unusual. Then one day, Hungerford peered down his microscope at the chromosomes of a white blood cell from a patient with CML and noticed something strange.

One chromosome was much smaller than it should be. Ever the photographer, he snapped a picture. This blurry black and white image is first evidence of the genetic origins of leukaemia in humans.

After this exact same tiny chromosome turned up in cells from seven different patients with CML, Nowell and Hungerford suspected it was definitely linked to the development of cancer, writing at the end of their 1960 paper “The finding suggests a causal relationship between the chromosome abnormality observed and chronic myeloid leukaemia.”

But many scientists were sceptical, and one brief paper wasn’t enough to convince them.

The prevailing theory at the time was that cancer was caused by environmental factors like exposure to carcinogenic chemicals or viruses. Undeterred, they continued their work, examining the chromosomes of more patients with CML.

Hungerford and Nowell went on to confirm that the majority of people with CML had the same small chromosome, which by then had become known as the Philadelphia chromosome. Eventually, researchers around the globe confirmed their findings, and we now know that 95% of CML patients have the Philadelphia chromosome in their cancer cells.

Initially scientists widely assumed that these usually short Philadelphia chromosomes formed thanks to the deletion of some genetic material from the ends of the chromosome. But in the 1970s, a researcher from the University of Chicago called Janet Rowley, the “matriarch of cancer genetics”, realised that this wasn’t the case.

Rowley was fascinated by examining the genetic origins of disease. She developed techniques for staining chromosomes and highlighting the bands on each chromosome, making them easier to identify and illuminating any unusual changes. Rowley set to work using her techniques to study the chromosomes of cancer cells.

When she looked at the chromosomes of white blood cells from patients with CML, she discovered that the Philadelphia chromosome wasn’t formed by a deletion of genetic material after all. The mutant chromosome formed when two chromosomes - 22 and 9 - got broken, and the two end pieces swapped places, a process known as translocation.

In this case, a tiny part of the larger chromosome, number 9, gets switched for the bulk of the already petite chromosome 22, creating a barely noticeably larger number 9 and a teeny weeny 22 - the infamous Philadelphia chromosome.

Building on Rowley’s discovery, in the 1980s Nora Heisterkamp and her colleagues at the National Cancer Institute showed that the break on each chromosome occurred in a specific position: at the ABL gene on chromosome 9, and the BCR gene on chromosome 22. So when the two pieces swapped places, the result was a fused, hybrid gene on the Philadelphia chromosome known as BCR-ABL.

Later experiments by Owen Witte at the University of California, Los Angeles, showed that the fused gene coded for an enzyme known as a tyrosine kinase. Although tyrosine kinase enzymes are common throughout the body, the enzyme made by the BCR-ABL gene is unusually active, resulting in the uncontrolled cell growth of white blood cells that characterises CML.

In just 40 years, we had gone from having no understanding of how CML developed to knowing in depth the genetic and molecular origins of the disease and having a potential target for a cure: the rogue BCR-ABL enzyme.

The hunt was on.

The search for a cure

Like many optimistic young researchers, Brian Druker, an oncologist at the Dana-Farber Cancer Institute at Harvard Medical School was determined to cure cancer.

He theorised that by understanding the mechanisms that led to cancer, he could figure out a way to selectively kill cancer cells without harming normal cells, avoiding the downsides of aggressive chemotherapy while still keeping cancer at bay.

“I saw cancer as being a tractable problem,” he told the Smithsonian magazine in 2011 “People were beginning to get some hints and some clues, and it just seemed to me that in my lifetime it was likely to yield to science and discovery.”

Druker’s search for a cancer that was mechanistically well understood and potentially ‘curable’ soon led him to CML. By this point, scientists already knew precisely which runaway enzyme was causing the disease, making it an obvious target for intervention.

Druker became a man obsessed, frequently staying in the laboratory until late at night and devoting himself to the search for a cure to CML, at the expense of his marriage. But his search wasn’t as simple as looking for a molecule that would inhibit this treacherous enzyme. First, he had to develop techniques for tracking and measuring the activity of the BCR-ABL enzyme so that he could observe the effects of any potential new therapy.

Despite his devotion, progress was slow. Eventually, the head of medical oncology at Dana-Farber told Druker that the project just didn’t seem to be going anywhere.

“It was awful,” Druker recalled to Smithsonian magazine. “I was depressed. But it forced me to say, Do I believe in myself? Am I going to make it, make a difference?”

Too stubborn to quit, Druker moved to Oregon Health and Science University and continued his crusade.

“When I moved here to Oregon, my goal was to identify a drug company that had a drug for CML and get that into the clinic,” he said.

For a long time it was a fruitless search and it looked like things were going nowhere… but then came the breakthrough.

A friend at the drug company Novartis told Druker about a new compound they’d made called STI571 that could block tyrosine kinase enzymes, but they weren’t sure what to do with it. Druker jumped on the chance to try it out, and he soon confirmed that STI571 inhibited the BCR-ABL enzyme that causes CML.

Next, Druker had to prove that the compound would slow or stop the growth of cancerous cells. And in his laboratory tests the cancerous white blood cells that were treated with the compound died while healthy cells were unaffected. It was the breakthrough Druker had been searching for.

Skeptics were quick to point out that the human body contained hundreds of different tyrosine kinase enzymes which the drug could block, causing potentially devastating side effects. But Druker soldiered on with his experiments undeterred, showing the drug eradicated CML in mouse models of the disease with no significant side effects.

Eventually, Druker gathered what he considered enough evidence to bring the therapy to clinical trials, but Novartis disagreed and in fact advised dropping the project. So, stubborn as always, Druker went straight to the FDA, who granted permission for human trials to proceed under Druker’s supervision.

The first clinical trial for STI571, now known as Gleevec, began in 1998, and it was a resounding success.

The trial participants had exhausted all other options for CML treatment and were waiting for death. The drug all but eliminated the disease. Of the 31 patients in the trial, 30 had normal white blood cell counts within a month. Further trials also had positive results, and after five years, 98% of people receiving Gleevec were still in remission.

Gleevec was approved by the FDA in record time in 2001, and hailed as a ‘miracle cure’ by the media, with good reason. Today, people with CML who respond to Gleevec can expect to live as long as someone without cancer. It is, in my humble opinion, arguably one of the greatest cancer drugs of all time.

One drug - which nearly got shelved - has transformed CML from a death sentence to a manageable, long-term disease, netting billions of dollars in profit for Novartis in the process. And its remarkable success fuelled an explosion of research to find the next blockbusting cancer therapy.

Druker himself hoped that the story of Gleevec could serve as a model for curing other types of cancer. “You describe a clinical entity, understand its molecular pathogenesis and use that knowledge to describe a specific therapy,” he said in 2010 presentation. But, as is often the case in science, particularly when cancer is involved, that is easier said than done.

After the success of Gleevec, researchers continued to look for more cancers caused by fusion genes and rogue molecules that they could target in a similar way, but so far, they have found relatively few other examples.

Still, there are plenty of targeted therapies on the market, and it is becoming standard practice to look at the genetic make-up of many cancers before deciding on a treatment. But alas, few are ‘magic bullets’, bringing the kind of survival gains that have come with Gleevec.

Unfortunately, the success of this wonder drug fooled us into thinking that cancer could be straightforward to treat just by targeting a specific genetic mutation. In reality, CML is the exception rather than the rule, because every cancer cell contains the rogue BCR-ABL fusion, and they’re all pretty similar.

Most other cancers are made up of a mish-mash of cells with many different genetic mutations, making them much more challenging to treat. And we also now know that cancers can evolve resistance to therapy, coming back with a vengeance later down the line.

But Brian Druker hasn’t given up on his dream of curing cancer.

He says, “For me, the future of cancer research is far more targeted therapy. The analogy I use is infectious diseases. A century ago, if you got an infection, that was fatal. But antibiotics and vaccinations and public health prevention programs were discovered—all targeted therapies. We can make cancer treatable and curable, or even eradicate it, over this next century.”

“If the cause has been discovered, there’s hope for a cure.”

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