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Ross Camidge, MD, PhD, clinical director of the Thoracic Oncology Program, was chugging away on a drug trial for Pfizer.
Stayi n g a ste p ah ead 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.
Chromosome kink causes cancer, is perhaps also its cure Every cell in your body holds the 20,000-or-so
Unfortunately, in a very special 3-to-5 percent
Like a kindergartner at a state fair, this
genes it needs to do things like grow fingernails
of lung cancers, chromosome No. 2 folds back on
ALK-fusion protein needs to eat sugar in
and solve the New York Times crossword. But
itself, like an inchworm bringing its back feet up
order to function, in this case the sugar-like
not every cell needs to do all these things, and
to just behind its front.
molecule ATP.
so your body turns these genes on and off as needed. For example, your body only needs the
ALK-fusion protein
ATP
gene that makes the protein ALK in the early stages of your developing nervous system. After you form your brain and other nervous goodies, the gene that codes for this ALK protein just sits there silently on inchworm-like chromosome
EML
4
ALK
No. 2, opposite another idle gene called EML4, twiddling its genetic thumbs and thinking deep thoughts about the weather.
EML4
ALK-fusion protein’s mouth—outcompetes, Now instead of exposing the code of its entire
ATP comes along, then the ALK-fusion protein
its head (ALK) and the gene on its tail (EML4).
can’t transmit its signal and the cell doesn’t replicate out of control.
That is, unless the gene is reactivated. age, sunbathe, or let the car door bang closed on your shins while unloading groceries, your
EML
4
ALK
cells die. And so you need new cells. Your body creates them by duplicating old cells. Only, sometimes your body’s copy machine goes awry, allowing mutations to sneak into the genetic
actually—and if its mouth is plugged when
belly, it shows a new code made from the gene on
A LK
When you do unkind things to your body like
But it can’t eat ATP if its mouth is plugged. Crizotinib competes with ATP for space in the
ALK-fusion protein
AT P
P
Paul Bunn, MD, holds an endowed chair— the James Dudley Chair in Cancer Research.
THE SCIENCE OF CRIZOTINIB
AT
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.”
DINGCANCER
ATP
P AT
codes of these new cells. Most of these mutations do everything
AL K pro-fusio tei n n
This squished-together code is the blueprint
or nothing—killing the new cell or making no
for an ALK-fusion protein—called a “kinase”—
difference whatsoever. A very few of these
which sends signals telling cells to grow, split,
crizotinib stops ALK-positive lung cancer cold
mutations lead to cancer.
and survive in an out-of-control, cancerous way.
while leaving healthy tissues unharmed. Trials
One of these oncogenic mutations is the
Crizotinib is an ALK inhibitor.
ALK-fusion gene.
The gist is this: by blocking its energy,
at the University of Colorado Cancer Center and elsewhere show that crizotinib halts the growth of 90 percent of ALK-positive, non-small-cell lung cancer patients. —Garth Sundem
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, creativity and 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.”
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C3: Winter 2011