Serendipity by Design

Serendipity by Design, Collaborating to Conquer Cancer, Fall 2011By Garth Sundem

In the University of Colorado Cancer Center’s fight against lung cancer, what looks like luck on an ordinary day is the product of forethought, experience, and a willingness to ride the winds of change.

In August 2007, Marileila Varella-Garcia went to Paul Bunn’s office to ask for $10,000. Research grants take months and Garcia’s intuition told her not to wait—the prestigious scientific journal Nature had just linked a type of lung cancer to a specific genetic mutation, and Garcia, PhD, renowned international expert on cancer cell genetics, wanted to know which patients had it. She needed $10,000 to develop the test.

Bunn is no slouch himself. At a 2010 conference of the American Association for Cancer Research and the International Association for the Study of Lung Cancer, Bunn was honored for his leadership in lung cancer research, with the conference chair calling him an “inspiration to physicians and scientists working in the field of lung cancer.”
Over the years, the handsome, grey-haired Bunn has built a world-class lung cancer treatment and research team at the CU Cancer Center, and was instrumental in bringing Garcia onboard in 1993. And because Paul Bunn holds an endowed chair—the James Dudley Chair in Cancer Research—he doesn’t live grant-to-grant, but instead has his own yearly research endowment to spend as he sees fit. By 2007, Bunn and Garcia had worked together for 14 years, and so when Garcia asked, Bunn trusted Garcia’s hunch and gave her $10,000 from his discretionary research account.

Garcia took it to the lab.

IMAGINE A CHROMOSOME AS AN INCHWORM

When the inchworm is stretched out, the pattern of its feet forms the blueprints of the body’s proteins. Now imagine this inchworm, inching—bringing its feet up to just behind its head. This is what chromosome No. 2 does in 3 percent of non-small-cell lung cancer patients. Instead of making a healthy ALK protein from the worm’s front half and a healthy EML4 protein from its back half, the bunched worm makes an ALK-fusion protein from the squished-together bits of tip and tail. This ALK-fusion protein causes lung cancer in about 45,000 people each year. Lung cancer in general remains the leading cause of cancer deaths worldwide.

In the world of cancer research $10,000 is a tiny drop in a mighty ocean, but it was this drop, dripped in just the right place, that allowed Garcia to develop a specific test for these ALK-fusion proteins in lung cancer patients.
“It’s a tricky test because the two partners are on the same chromosome and not far apart, and when they fuse they’re on the same gene not so far apart,” Bunn says.

Relying on her experience, her expert research team, and the center’s Cytogenetics Shared Resource, which she directs, by the end of November 2007, Garcia had her test.

MEANWHILE, LUNG CANCER PATIENTS WERE FIGHTING FOR THEIR LIVES

Dr. Paul Bunn and Dr. Ross Camidge, lung cancer doctors at the University of Colorado Cancer CenterElsewhere at the CU Cancer Center, Ross Camidge, MD, PhD, clinical director of the Thoracic Oncology Program, was chugging away on a drug trial for Pfizer. Patients in the study were tested for a different mutation, one in the MET gene, and the drug Camidge’s patients were taking through the center’s Developmental Therapeutics Clinic was supposed to nix the function of this faulty gene.

The phase I safety trial of this drug was taking place at a number of hospitals around the country, notably also at the juggernaut of Massachusetts General Hospital in Boston, but because the CU Cancer Center was the only site in the west, “We got patients from California, Washington, Las Vegas,” Garcia recalls.

In this large trial, little CU was a close second to Mass General in patient enrollment.

As can be the case with these safety studies, some patients responded while others didn’t, and overall the drug was showing only middling results. The goal isn’t to find out if the drug works, but rather what side effects happen at different dosages or schedules. But then the news of this new cancer-causing gene, ALK, broke in the journal Nature—and Pfizer quickly changed the tune of its clinical trial.

The drug that Camidge and others were testing didn’t just nix the first target, MET, but also nixed the function of this newly described ALK-fusion gene.

Maybe it wasn’t that Pfizer’s drug didn’t work, but rather that they were giving it to the wrong patients? It’s like offering macaroni and cheese to a food critic and a 5-year-old: The same meal makes one salivate and the other cringe. Pfizer decided to see how its drug worked with the patients who salivated, the ones with ALK-fusion genes.

Pfizer asked who among its participating centers could test for this ALK-fusion gene.

GARCIA RAISED HER HAND

There were only two places in the country with the ability to test for this gene: Mass General and, due to Garcia and Bunn’s foresight, the CU Cancer Center.

“Because we could do the molecular test here, we became a partner and not an outpost,” Garcia says.

In 2008, Pfizer hired Mass General and the CU Cancer Center to run these genetic tests and enroll ALK-positive patients into a phase I clinical trial of their drug. “Camidge got patients, he would send their samples to me, and in three days he knew if they were ALK-positive,” says Garcia.

“You spend all your time planning things and then stuff just happens and you have to run with it,” Camidge says.

Because the CU Cancer Center is comparatively nimble, it was able to sprint.

The center soon started testing patients with Garcia’s molecular spyglass and enrolling them on a refocused trial of Pfizer’s drug. The results were dramatic.

“When one patient shows a benefit, it might be a fluke,” Bunn says. “But when the number gets to ten, you know you have something special.”

Marileila Varella-Garcia and members of her lab at the CU Cancer Center

ONE OF THESE PATIENTS WAS ELLEN SMITH

After being diagnosed with lung cancer in 2008, Smith had undergone a spring and summer of chemotherapy followed by surgery to remove her left lung and then radiation through the fall. Finally, “The doctor came in and the news was spread all over his face,” Smith says. “My lung cancer had spread to five places in my abdominal cavity. He was a great doctor, but basically he said, ‘I don’t know what else I can do for you.’ ”

Her doctor was right; there was nothing more he could do. In fact, there was nothing that standard medical science could do.
But Ellen Smith says, “My family and I weren’t ready for that.” Smith has three grown children, five grandchildren and was in a relationship with a man she called her “longtime gentleman friend.” It wasn’t a convenient time to die.

In another serendipitous turn, Smith had retired from her job as a public school teacher and was working as a nanny for a mother who is a thyroid cancer researcher at the CU Cancer Center.

Ellen Smith is a lung cancer patient at the University of Colorado Cancer Center, here with her granddaughter Lucy.She said, ‘Ellen, you have to go to the CU Cancer Center.’ She twisted my arm until I went there for a second opinion,” says Smith.

And there at the CU Cancer Center, Ellen Smith stumbled into Camidge, Garcia, Bunn, and a melting pot of scientists and doctors who had spent years preparing for her arrival. She signed a consent form to have her tumor specimen tested, and then she went to Scotland with her gentleman friend to retrace her family roots. It was something she had always wanted to do, and with cancer shutting down her body, it seemed like now or never. She almost didn’t survive the trip. In Scotland, her remaining cancer-blackened lung started bleeding, and she was rushed to the
emergency room.

“I was in a foreign country, and I was so frightened,” Smith says. Then, on what she thought was her deathbed in a foreign emergency room, Ellen got a long-distance call from her son. She was a match for the CU Cancer Center clinical trial. Ellen Smith was among the ALK-positive 3 percent. She flew home to Camidge.

By this time Pfizer’s drug had a name—crizotinib—and it ripped Ellen Smith back from the precipice on which she had been standing. Crizotinib works by starving ALK-positive tumor cells of their energy source, and as Ellen’s tumors starved, they shrank by more than 40 percent.

Of the 82 ALK-positive patients enrolled in what was supposed to be a trial assessing only the drug’s safety—a test of the medicine in patients beyond hope who had little to lose if the drug proved unexpectedly dangerous—90 percent saw their tumors stabilize or shrink, and 57 percent saw their tumors shrink by more than a third.

“It was as if their tumors melted away,” Bunn says.

LIFE AFTER HAPPILY EVER AFTER

Most fairytales end here, but creating remission is only a step on the path to a cure. “Dr. Camidge told me that a day would come when the ALK inhibitor wouldn’t work,” Ellen Smith says. “That day came about a year and a half later.”

“What do you do when the honeymoon ends, when these people who responded fantastically start to become resistant?” Camidge asks. Cancer is insidious—the same mechanism that allows healthy cells to mutate into cancer cells also helps cancer cells mutate around the barricades of treatments.

First, just as we’ve seen that two lung cancers might not be created equal, so too can pockets of cancer within a patient’s body evolve differences over time. In Ellen Smith, when a follow-up scan showed that just one of her tumor deposits had become resistant to crizotinib, CU Cancer Center radiation oncologist Brian Kavanagh, MD, MPH, was able to blast just this tiny part with stereotactic body radiation. In fact, Kavanagh literally wrote the textbook on stereotactic radiation, which was published in 2004—just another world expert who was fortunately part of Ellen Smith’s treatment team.

“This radiation just deletes one little bit of your body,” Camidge says. “It’s very good for weeding the garden. You don’t throw the baby out with the bath water, just zap the resistant part of the tumor and keep the drug going.”

Eventually all of Ellen’s lung cancer became resistant, and the crizotinib honeymoon was officially over. At that point, most oncologists would’ve been back to the drawing board, guessing at a treatment that could put another barrier in lung cancer’s way.

The CU Cancer Center did better than guess.

KNOWING YOUR PATIENTS LEADS TO PATTERNS

“One thing that comes from getting to know your patients is learning to listen to them when they tell you about what worked well or what didn’t,” Camidge says. “For example, a 35-year-old man on crizotinib told me he had a new girlfriend, but wasn’t finding her as attractive as he should.” Sure enough when they checked this man, his testosterone was low. In fact, when he checked, 100 percent of Camidge’s male patients on crizotinib developed low testosterone, which, once discovered, was easy to replace.

“We now check testosterone on all our crizotinib patients, and I think this will change the way the drug will safely be given in the future. The only way you get to find out this sort of thing is if you know your patients as people so that they’re comfortable telling you about the intimacies of their lives,” Camidge says. “With a big center, there are more patients, but they may be spread around across multiple doctors and it becomes harder to spot these subtle patterns.”

Working with Camidge, new Australian senior fellow Andrew Weickhardt, MD, was the first to pull together the testosterone data from Camidge’s original observation. Recently Weickhardt submitted the important findings for publication. “Returning a young man’s testosterone to normal is something he is pretty grateful for. It gives them an important piece of their life back,” Weickhardt says.

Spotting another lucky pattern helped Camidge save Ellen Smith’s life a second time. Because these ALK-positive patients had been treated with crizotinib as a therapy of last resort, they’d commonly tried upwards of five other drugs before starting the crizotinib trial. Camidge noticed that before their cancer had developed resistance, many of these ALK-positive lung cancer patients had done surprisingly well on a drug called Alimta.

“There’s nothing quite like that feeling—like you’re in school and everybody’s doing a math calculation and they all get different answers, but you have this little voice that says maybe they’re all wrong and you’re right and you just stick to your guns,” says Camidge.

He was right about this: If a patient hadn’t seen Alimta before moving down the line to crizotinib, then when lung cancer developed resistance to crizotinib, this Alimta was a spectacular next line of defense. When Ellen Smith’s crizotinib honeymoon ended, as she had never seen Alimta before, Camidge immediately started her on it.

“Confirming the earlier pattern seen with other patients, Ellen had almost as dramatic a response on the Alimta as she did on the crizotinib,” Camidge says. “She’s been on
the Alimta for nine months (in Sept. 2011) and I can’t see any sign of active cancer on her scans.”

STAYING A STEP AHEAD

But lung cancer never rests, and so CU Cancer Center doctors are already laying the groundwork for Ellen Smith’s next step.

For example, pathologists Wilbur Franklin, MD, and Dara Aisner, MD, whom the CU Cancer Center recently enticed away from the University of Pennsylvania, are growing samples of patients’ tumors in the lab to discover how they evolve around drugs like crizotinib and Alimta. Franklin created the Colorado Molecular Correlates Laboratory, perhaps the nation’s most accomplished facility for testing for genes that drive tumors. In this lab, Franklin grew a large culture of cells from a small sample of Ellen Smith’s tumor. And Aisner developed tests that can tell exactly how these tumor cells develop resistance to drugs.

Still another cook in this crowded kitchen, Robert Doebele, MD, PhD, connects the dots from the tumors of patients like Ellen Smith through Franklin’s cells, using Aisner’s test, to recommendations for the next line of drugs that will hit Smith’s evolving tumor from an angle it hasn’t yet learned to protect, if and when needed.

This flock of therapies developed by a gaggle of scientists and administered by a covey of doctors has kept Ellen Smith alive.

“I’m three years out now,” Ellen Smith says. In that time—that extra time—Ellen married the person she calls her “wonderful gentleman friend.” And then on July 12, 2011, her sixth grandchild was born. “Her name is Lucy and I’m just so completely in love,” Smith says. “I see her twice a week. I go for walks with my daughter and see my granddaughter.” Because of crizotinib and the CU Cancer Center treatment team that has consistently stayed a step ahead of her cancer, Ellen Smith is walking with her family instead of walking in their memories.

Charles Goodyear invented vulcanized rubber when he spilled a mixture of rubber, sulfur and lead onto a hot stove. Wilson Greatbatch invented the pacemaker when his attempt to monitor heart activity regulated its rhythm. DuPont chemist Roy Pluckett invented Teflon when the gas he was working with cooled into flakes. And on August 26, 2011, vaulting past the usual steps of phase II and III trials, the FDA approved Pfizer’s drug crizotinib, which serendipity in the form of Garcia’s test of Camidge’s patients had plucked from the trash bin of a struggling trial.

But was it serendipity? Louis Pasteur said, “Chance favors the prepared mind,” and in this case, the CU Cancer Center as a whole was that prepared mind. It was ripe for serendipity because Paul Bunn, Marileila Varella-Garcia, Ross Camidge, Andrew Weikhardt, Brian Kavanagh, Dara Aisner, Wilbur Franklin, Robert Doebele and all the other doctors and researchers—small in number but world-class in expertise, creativityand motivation—had built it that way.

“We’re small enough that I could walk down the corridor and knock on Leila’s door and knock on Bob’s door,” says Camidge. And this melting pot of researchers, just big enough to have everything Ellen Smith needed but small enough to remain mixed and nimble, spawned a treatment with the potential to save 45,000 lives a year—that’s two-thirds of the average crowd at a Denver Broncos game.

Imagine sitting in a nearly empty stadium. Now imagine sitting in a full one. That is the difference of the drug crizotinib.

Andrew Weickhardt says, “No one thinks we’re going to pack up our bags and go home tomorrow, but the future seems brighter than it has for a long time in fighting lung cancer.”

About the author: Garth Sundem

In addition to writing for the University of Colorado Cancer Center, Garth is the author of the books The Geeks' Guide to World Domination, Brain Candy, and Geek Logik. Contact him at garth.sundem [at] ucdenver.edu.

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