February 8, 2017 | by Abe Rosenberg
Let's say you're a carpenter, and you're building a cabinet.
No problem, you're pretty good at it. But suppose you happen to meet a computer whiz with a modeling program that can design a super gorgeous cabinet? And what if the two of you then bump into a chemist with a formula for treating wood that'll make that cabinet practically indestructible? Then, what if the three of you meet up with a mathematician with an algorithm enabling you to build bigger, better and cheaper? Wouldn't that be amazing? All that help from folks who never picked up a hammer in their lives!
Welcome to the future of cancer research.
Scientists and clinicians alike have figured out that in this era of precision, targeted therapy that digs down into the very DNA of disease, it's necessary to venture beyond their own labs for answers.
Tomorrow's breakthroughs will require a multidisciplinary approach: medical people working hand-in-hand with physical scientists, data crunchers, nanotechnologists, digital imaging specialists and more. Pulling together such a disparate team requires a special kind of vision and leadership.
And few people do it better than Peter Lee, M.D.
I try to take a ‘big picture’ approach to solving problems,” said Lee, the Billy and Audrey L. Wilder Professor in Cancer Immunotherapeutics who chairs City of Hope's Department of Immuno-Oncology. “So many traditional scientists begin with something complex and break it down to just one thing, in isolation. That doesn't translate into real-world help for patients.”
He's been helming multidisciplinary teams for more than a decade, starting with a U.S. Army grant in 2005 in which he brought together statisticians, computer scientists and clinicians to study breast cancer.
In his latest “big picture” project, Lee directs a diverse, far-flung team (“lots of emails, phone calls and plane flights ... a real challenge,” he said) that's examining breast tumors' so-called “microenvironment,” or the noncancerous cells that surround and support the tumor, and how they affect the immune system.
Team members include a theoretical physicist from University of California, Irvine, a quantitative biologist from New York's Cold Spring Harbor Laboratory, an engineer from Massachusetts Institute of Technology and a physical scientist from Rice University.
It's this kind of ambitious, never-before-tried approach that truly excites Lee, and he's found kindred spirits at the Stand Up To Cancer (SU2C) Foundation, which is funding his team, with additional help from the Breast Cancer Research Foundation, the V Foundation and Bristol-Myers Squibb, in a kind of “combo” grant. SU2C calls it a “convergence translational research” team.
So what does that mean in English?
“Stand Up To Cancer cares about finding an original group of people that can do what one person cannot,” said Arnold J. Levine, Ph.D., a SU2C scientific advisor and supervisor of Lee's team. “We had the idea of forming teams from different institutions, people who are the best at what they do, from anywhere in the world, to create a great synergy in fighting cancer.”
To achieve that synergy, SU2C brought together 120 applicants who spent a week brainstorming, competing, collaborating, arguing and making presentations (“It was speed dating for scientists!” said Levine, laughing). Eventually the field was winnowed down to four teams, each with a novel idea for attacking cancer. It was decided in advance that a clinician who actually treats patients would lead each team, and Lee, whom Levine calls “gifted,” was the natural choice to head the breast cancer project.
“He's a serious guy who really cares,” said Levine, pointing out that Lee takes what he learns from his patients and reintegrates it into his lab. “Not every clinician does science the way he does.”
And not every cancer scientist enters the field in the same manner as Lee did.
His first foray into research had nothing to do with cancer.
At the height of the AIDS crisis in the 1980s, Lee was an undergrad studying microbiology. He thought he saw a way to create antibodies that would block one of the molecules that HIV needs to enter T cells. Although that project didn't pan out, it sparked his interest in the immune system.
Later, in medical school, Lee saw how leukemia patients suffered through the effects of chemotherapy. He resolved to find a better way to treat cancer.
Putting his own spin on the subject, Lee felt that instead of examining in the minutest detail a tumor's every last molecule, it made more sense to observe changes in immune cells located in the presence of that tumor. In pursuing that goal, Lee was bucking conventional wisdom.
“The dominant view at the time was that the immune system had nothing to do with cancer,” he said. “But I was pretty pig-headed about it. I was convinced that cancer cells are the ‘offense,’ immune cells are the ‘defense,’ and how they play together determines the outcome.”
Pig-headedness has paid off.
In 17 years at Stanford and five years here at City of Hope, Lee has made several remarkable discoveries and pursued unique avenues. Among them:
Contrary to “conventional” wisdom, the immune system does engage when cancer threatens to strike. “We've been able to show, in melanoma for example, that in at least half the cases, the immune system mounted a response, but it was ineffective,” he said.
Those immune responses fail for more than one reason. While it's known that some cancer cells are clever enough to “evade” immune cells, it now appears that some malignancies go even further, actually modifying those disease-fighting cells, rendering them useless.
Another revelation: Tumors are not just collections of cancer cells. They also contain support, or “stromal,” cells and immune cells. This is the microenvironment that turns out to be so important.
Stromal cells nourish the cancer, protect it and help provide a pathway for growth. The number and nature of those stromal cells has been shown to have a direct impact on the effectiveness of treatment ... or lack of it.
The same is true of immune cells. In breast cancer, tumors with more stromal cells typically have worse clinical outcomes. Tumors containing a type of immune cell called CD8 T cells have better clinical outcomes.
Over the next three years, Lee and his team will use their combo grant to learn more about all these phenomena, possibly leading to new and better forms of immunotherapy, targeted therapy and precision medicine.
His colleagues believe he's onto something.
“We’ve only begun to understand how the tumor microenvironment modulates cancer both from a growth and suppression perspective,” said David Horne, Ph.D., vice provost and associate director of Beckman Research Institute of City of Hope. “The more we can unravel these complex interactions, the more we'll understand how to develop more effective therapies involving the tumor microenvironment, rather than just the tumor itself.”
And Lee has a head start.
“Peter has done remarkable work creating 3-D images of breast tumors that clearly show the activity of those stromal cells,” added Levine. “The members of his team will be able to mine an incredible amount of data from those images ... and, using their own expertise, they'll take this research very far. That's why they got the grant.”
For Lee, all this is validation, as well as incentive.
He loved his time at Stanford, where he was a tenured professor. But at City of Hope he's escaped what he calls the “academic rat race” to concentrate on real results.
“What matters to me most,” he said, “is the focus on the patients. I want to bring them the results of my research.”