The hero scientist who defeats cancer will likely never exist.
No exalted individual, no victory celebration, no Marie Curie or Jonas Salk, who in 1955, after he created the first polio vaccine, was asked, So what’s next? Cancer? — as if a doctor finished with one disease could simply shift his attention to another, like a chef turning from the soup to the entrée.
Cancer doesn’t work that way. It’s not just one disease; it’s hundreds, potentially thousands. And not all cancers are caused by just one agent — a virus or bacterium that can be flushed and crushed. Cancer is an intricate and potentially lethal collaboration of genes gone awry, of growth inhibitors gone missing, of hormones and epigenomes changing and rogue cells breaking free. It works as one great armed force, attacking by the equivalent of air and land and sea and stealth, and we think we’re going to take it out with what? A lab-coated sniper?
“This disease is much more complex than we have been treating it,” says MIT’s Phillip Sharp. “And the complexity is stunning.”
So it will take not one hero but many. Sharp — a Nobel Prize-winning molecular biologist who studies the genetic causes of cancer — is recruiting special-forces units to fight back. For the past four years, he has been wrangling dream teams funded by Stand Up to Cancer (SU2C), an organization started by entertainment-industry figures unhappy with the progress being made against America’s most deadly disease. Cancer still kills in large numbers: an estimated 580,350 people will die of the disease in the U.S. this year, according to the National Cancer Institute. Another 1.7 million cases will be diagnosed, and those figures will grow as the population ages.
Cancer research — indeed, most medical research — is typically about the narrowly focused investigator beavering away, one small grant at a time. But advances in genetic profiling of malignancies and the mutations that cause them are telling scientists and physicians they must stop working in these kinds of silos, treating lung or breast or colon or prostate cancer as distinct diseases. “You no longer do science and medicine differently,” says Dr. Lynda Chin, director of the Institute for Applied Cancer Science at MD Anderson Cancer Center. “It brings science and medicine together.” Common genetic mutations, like one called p53 that controls cell death, are showing up across a whole swath of cancers. A mutation called BRCA1 is common in women’s cancers such as breast and ovarian, yet the research and clinical work in those two diseases has largely been separate.
So what does it take to transform the way an entire medical ecosystem functions? In this case, an unprecedented combination of celebrity, intensity and unignorable amounts of money. In 2008 a team including Spider-Man producer Laura Ziskin, who lost her battle with breast cancer in 2011; Katie Couric, who lost her husband to colon cancer in 1998; and former Paramount CEO Sherry Lansing founded SU2C with the goal of attacking cancer the way you make a movie: bring the best and most talented possible people together, fund them generously, oversee their progress rigorously and shoot for big payoffs — on a tight schedule.
SU2C raises money through foundations and corporate, organizational and private donors and then grants it to teams in the form of unusually large sums (up to $18 million, vs. about $500,000 for a typical grant from the National Institutes of Health, or NIH) to produce results in an aggressively short time, initially three years. All the chosen projects are monitored by the American Association for Cancer Research. An SU2C scientific committee, headed by Sharp and other heavy hitters, reviews each team semiannually, a checkup that can make top scientists feel like grad students.
“When you have to answer to Nobel laureates and others, it’s a very tough review team,” says Dr. Daniel Von Hoff, Chief Scientific Officer at the Virginia G. Piper Cancer Center at Scottsdale Healthcare and physician in chief at the Translational Genomics Research Institute, a dream team launched by SU2C that’s studying pancreatic cancer. “You want to be at your best.” Says Dr. Lewis Cantley, head of the cancer center at Weill Cornell Medical College and New York — Presbyterian Hospital in New York City: “Having people review you every six months is very different. The model is really unique.”
The team model is also disrupting the normal course of business across the medical-research community. For investigators, it means changes in the way careers are developed, the way data — and especially credit for achievement — are shared. For institutions, team research means changes in contracts, compensation, titles and the path of intellectual property. For pharmaceutical companies, it means restructuring the way experimental drugs are allocated and clinical trials are conducted.
And yet what started in Hollywood is now being embraced by the very heart of the research establishment. NIH, which has parceled out its $5.5 billion cancer-research budget to a single principal investigator for each grant it makes, is recognizing the paradigm shift necessitated by the torrent of data pouring forth from genomics. NIH boss Dr. Francis Collins, who led the team at the Human Genome Project, says that under his watch, the 27 institutes he oversees will be less independent fiefs pursuing their own goals and more trustworthy collaborators that can be teamed up to answer common and complex biomedical questions. “I am strongly anti-silo, strongly pro — breaking down barriers, bringing disciplines together, building collaborations and building dream teams,” he says.
And for patients, it’s happening where the chemo hits the cancer. Dr. Ronald DePinho, president of MD Anderson Cancer Center, is adopting a similarly collaborative approach around what the world-renowned institute calls its Moon Shots program, assembling six multidisciplinary groups to mount comprehensive attacks on eight cancers: lung, prostate, melanoma, breast, ovarian and three types of leukemia. For DePinho, this is a $3 billion throwdown. He’s backing his teams massively, with plans for $300 million annually over the next decade by reallocating existing research funds and soliciting new donations. As in the SU2C effort, teams will be judged by patient outcomes, not by the number of research papers published. “Aspiring is not enough. You must achieve,” he says. “It’s about integration across the entire cancer continuum, and it’s about execution. People will be judged by whether they have reduced mortality in cancer.”
It’s a measure, perhaps, of what a quagmire the war on cancer has become that the basic premise of the whole enterprise — that this is about reducing mortality, saving lives — requires repeating.
One Small Victory at a Time
As if the non-small-cell lung cancer that had defied conventional therapies had not been enough, the tumors in and around Tom Stanback’s lungs grew so large that he was having difficulty swallowing and breathing. Unwilling to go quietly, Stanback actively sought out clinical trials (surprisingly, most patients don’t) in search of anything that might extend his life. One of them, at Johns Hopkins in Baltimore, is focused on studying the enzymatic on/off switches that sit atop the underlying genome and regulate whether and how loudly those genes will be expressed. This includes the mutated genes that crank out cancer cells. While science can’t do much to change the genome, epigenetic functions are manipulated all the time — sometimes inadvertently, by exposure to environmental chemicals, say; other times cleverly, by drugs. Stanback, a 62-year-old, 40-year former smoker, was involved in a trial to see if a new epigenetic drug could shrink his tumors.
In his case, the answer was no, not quite. But the leaders of the cross-disciplinary, cross-institutional research team behind the work (one of nine, soon to be 10, main teams backed by SU2C) weren’t finished. They postulated that even if the epigenetic manipulation alone didn’t knock out the cancer, it had a priming effect, improving the likelihood that other treatments administered later would work. That’s exactly what happened when Stanback returned home for a round of radiation therapy at Memorial Sloan-Kettering Cancer Center in New York City and joined a second clinical trial. His tumors have shrunk markedly in the past year and a half and were not visible on a recent CT scan. “The drug nudges the T cells to being alive and active,” he says. “I’m alive. I’m healthier than I’ve ever been.” Even better, a few other patients in the study have enjoyed what appears to be complete remission.
The team behind these victories is led by Dr. Stephen Baylin, an oncologist at Johns Hopkins, and Dr. Peter Jones, a biochemist and molecular biologist at the University of Southern California. They ride herd on a diverse group of experts — geneticists, pathologists, biostatisticians, biochemists, informaticists, oncologists, surgeons, nurses, technicians and specialists who normally wouldn’t have been working as an ensemble. The team was awarded its grant in May 2009 and within the year was able to extend the epigenetic clinical trial that enrolled Stanback and launch new ones. That is light speed in modern research — the lab to clinic cycle in cancer is typically a decade.
This kind of institutional transformation is not easy, but it’s the only way to take advantage of the dazzling scientific and technological advances that have taken place in just the past three years — advances in bioengineering, nanotechnology, drug compounds and data gathering, including protein data, splicing data and mutation data, all of which is being hoisted into view by ever cheaper computational muscle. Sequencing the first human genome took more than a decade and $2.7 billion. Today sequencing can be done for a few thousand bucks in a few hours.
That progress has led to similar pharmaceutical leaps. Hundreds of drug agents are in development for therapies targeting the genetic mutations that have thus far been identified. Some, as in the case of Stanback’s trial, seek to reactivate the body’s immune system. Others are designed to cut off a tumor’s blood or energy supply; still others seek to restart apoptosis, the programmed cell death that normally takes place in healthy bodies. New biomarkers are allowing doctors to identify, target and track cancer cells. “It happened, and it happened quickly,” says DePinho. “If you look back on the progress that we made, it was against not having a periodic table of cancer, of not being able to understand genes, of not being able to model.”
DePinho’s use of the moon-shot analogy is not a marketing gimmick. In 1961, when President John F. Kennedy announced that the U.S. was going to the moon, the idea was no longer science fiction. The physics were understood. What remained was a giant engineering project: apply enough money and aerospace engineers and you eventually get to Neil Armstrong’s giant leap for mankind. When President Richard Nixon announced the war on cancer in 1971, victory wasn’t remotely possible. It was as if someone had announced a moon shot in 1820, says Cantley.
Today the physics of cancer are known; what remains is massive engineering. “In the old days, everyone knew it took 30 years to test a compound,” says Dr. Daniel Haber, director of the Massachusetts General Hospital Cancer Center. Scientists got that to an eight-to-10-year process. Teams of researchers have whittled it down to a two-year timeline from the discovery of a specific mutation to a drug to treat it. That’s fast by most measures — but not fast enough if you’re a patient. Says Haber: “Cancer doesn’t wait two years.”
Despite that urgency, shifting to a team model will not happen overnight, in part because the sociology of medical research isn’t, in fact, very social. Historically, the principal investigator wins grant money for a proposal and takes top billing on everything from publications to patents to the glory that goes with them. Those in turn are crucial to getting more grants. It is self-perpetuating and self-limiting and over the past decade has increasingly stifled young investigators in particular because the percentage of grant applications that are funded by NIH, the so-called pay line, is now below 10% and falling.
Team science demands that alpha researchers work with other top dogs and share the investigation, the data and the credit. Baylin and Jones, leaders of SU2C’s epigenetics team, were rivals for years. “It does take an ego to do this business,” says Baylin, “because everybody is more than ready to tell you you’re wrong.” For these two, things have thawed so much that their families have vacationed together.
Haber, an oncologist, has similarly partnered with Massachusetts General biomedical engineer Mehmet Toner to lead an SU2C-backed team that has designed and built a smart chip device to trap circulating tumor cells (CTCs) in a blood sample. Many tumors release cells into the bloodstream; if a CTC finds purchase in another organ and starts to grow, that is metastasis. The breakaway cells are not easy to spot — there are a billion blood cells for every one of them — but detecting their presence is critical to stopping their spread.
The business-card-size detector the team built uses antibodies that bind to certain cell proteins to isolate and capture the CTCs. It’s possible the device will change the standard of care for treating several cancers, beginning with metastatic prostate cancer. The CTC chip’s role as a hunter-trapper is also being applied to lung cancer, where mutations can help direct powerful new therapies, to see how CTCs change and evolve during the course of treatment. With other cancers, like pancreatic cancer, where there are currently no mutations that can be targeted, CTCs are being analyzed to see if they can reveal new vulnerabilities in tumor cells.
Lassoing a single blood cell is complicated enough. But the pairing of bioengineers with oncologists was no small thing either, at least until they were thrown together by the SU2C grant. “The field had a bad rep and wasn’t moving forward,” says Haber, “but they learned DNA, and we learned equations.” His team even includes an entrepreneur-in-residence, Dr. Ravi Kapur, who was in charge of rolling out the prototype to the team’s collaborating institutions.
Big Pharma, Big Results
Cancer is a thief and biological con artist, breaking into and taking control of the mechanisms of a cell and coaxing it to grow and divide in dangerous ways. Cantley has spent a career chasing this cellular saboteur by, as he describes it, “teasing out signaling pathways” that govern not just growth but the very life span of a cell. If the malignant signaling can be silenced or reversed, the cancer won’t spread. In pursuit of that, he is now a co-leader of a team backed by SU2C that targets a pathway called PI3K, short for phosphoinositide 3-kinase. The pathway is a known driver in three women’s cancers: ovarian, endometrial and especially breast, which involves the PI3K mutation in 30% of cases. Says Cantley: “It’s the most frequently mutated oncogene in cancer.”
Drug companies have long been targeting mutations like this one to develop compounds that will interfere with the defective biochemical gateways. There are hundreds of drugs that may have some effect against some of the mutations, which sounds like an abundance of riches — but it’s also an abundance of complexity. That’s one reason that the pharma industry has a 95% failure rate for new products and that half of Phase III trials — the last step before approval — don’t cut it. “If I have 100 different drugs I can use in combination, then 100 times 100 is 10,000. You can’t do 10,000 trials,” says Sharp. But which ones can you do and should you do and on which patients? Since PI3K mutations are the most common type, those seemed like a perfect place to start for Cantley’s dream team, which is co-led by Dr. Gordon Mills of MD Anderson — another world-class PI3K pathway investigator — along with women’s-cancer specialists from Massachusetts General, Dana Farber (Harvard), Vanderbilt, Columbia University, Beth Israel Deaconess and Memorial Sloan-Kettering.
The goal is to launch trials as rapidly as the geneticists and biochemists solve the equation of matching mutations with drug compounds. In one of the best examples of the new model, Cantley, Dr. Gerburg Wulf and another researcher, José Baselga, proposed combining a PI3K inhibitor with a PARP inhibitor to combat a particularly pernicious mutation in the BRCA1 gene that results in high risk for developing ovarian cancer and a severe type of breast cancer known as triple-negative. PARP is the abbreviation for a group of enzymes that do repair work on damaged DNA strands — usually a good thing, unless the strands are producing cancer cells. Working on mouse models, the team got cures for BRCA1 mutant and triple-negative breast cancers when they combined a PI3K inhibitor and PARP inhibitor, which had never happened with other therapies.
Moving on to a human trial was also easier than it ordinarily is and illustrates what the new paradigm means for Big Pharma. The team needed a PI3K inhibitor from Novartis and a PARP inhibitor from AstraZeneca. Neither drug is approved for cancer treatment, and it’s rare to conduct a trial in which two unapproved drugs are combined. Because of concerns about intellectual property and other issues — no drugmaker wants to be smeared by the toxicity of another’s drug — companies are wary of collaboration. The success of the Cantley-Mills team had drug firms lining up. “Every company that had a PI3K inhibitor called me and asked would I work with them,” says Cantley. The result was almost without precedent: a human trial at five institutions with two unapproved drugs from two companies within about a year of discovery. “Four years ago if you said you were going to do that, you would have been laughed out of the room.”
The Big Targets
For all the progress made against some types of cancer, there are others that have never been anything but bad news. Take pancreatic cancer, an area that Sharp bluntly labels “a disaster.” The disease is often discovered in a late stage, and most tumors are inoperable. It has what researchers call bad biology — cancer cells that resist treatment. The goal of Von Hoff, who leads SU2C’s pancreatic dream team along with Dr. Craig Thompson, CEO of Memorial Sloan-Kettering, is to improve survival rates. Currently, less than 25% of patients with advanced pancreatic cancer make it to one year.
The focus of the 28-person team scattered across five institutions is to better understand the metabolic changes that characterize pancreatic cells. It’s a collaborative exercise that starts when surgeon Jeffrey Drebin of the University of Pennsylvania removes a tumor from a diseased pancreas. He carries it from the operating room to a lab, where it is flash-frozen for preservation. Penn’s lab sends a specimen to the Salk Institute’s Gene Expression Laboratory, where researcher Geoffrey Wahl and colleagues analyze the state of stellate, or star-shaped, cells that are usually involved in tissue repair but may play a role in cancer as well. Another sample goes to Princeton, to the lab of Joshua Rabinowitz, who analyzes amino acids, sugar and up to 300 metabolites. Team members at Johns Hopkins and Translational Genomics analyze the genome sequence.
One of the theories emerging from this group is that pancreatic cancer cells communicate with stellate cells that also show up around the tumor and conspire to ward off immune responses and build resistance to chemotherapies. The tumor cells seem to leech glutamine and other amino acids from the rest of the body to feed the tumor — one reason people with pancreatic cancer lose so much weight. Prevent the hijacking of glutamine and other amino acids and perhaps the tumor starves. The team has also discovered that vitamin D can help stop the scarring around the cancer, giving the immune system or chemotherapies better access to cancer cells.
Within two years, they had modeled, evaluated and tested an albumen-containing drug that shows promise in increasing the efficacy of treatments. They enrolled 861 patients in a Phase III clinical trial of a treatment for advanced pancreatic cancer that adds the chemotherapy drug Abraxane, and the results have been encouraging: the combination stabilized the disease in 48% of the patients, doubling the two-year survival rate — to 9%, which tells you how diabolically difficult the cancer remains. Remarkably, though, a few patients have had a complete remission. “This combination is a new standard,” says Von Hoff, “and most important, one that you could build on. This kind of broke the logjam.”
Something similar is happening at MD Anderson, where physicians and researchers who may have worked separately on breast cancer and ovarian cancer, for instance, are joining forces because the genetic markers are telling them the cancers are related. Exploiting connections, says Dr. John Heymach, an oncologist at MD Anderson who is part of an SU2C dream team focused on circulating tumor cells, “is where team science becomes important. It’s a pattern-recognition exercise. We are going to accumulate data and expertise. We are going to profile all these different mutations.”
Bree Sandlin is among the thousands of patients at MD Anderson rooting for the Moon Shots program. She’s a 37-year-old marketing executive for Shell who has twin boys and triple-negative breast cancer — so named because receptors for estrogen, progesterone and a growth factor known as HER-2/neu are missing. This makes treatment difficult, since those are targets for hormone and drug therapies. She’s in a clinical trial that is testing the effectiveness of eribulin, a cancer drug typically used in metastatic breast cancer, as an adjuvant — an immune-system kick-starter. So far, it’s working well. “That approach to research is just very different than how they used to approach it in the past,” she says. “It can’t help but give me hope.”
More hope for other potential patients is coming from the new platforms MD Anderson has added around prevention and early detection. If patients like Sandlin are genetically predisposed to breast cancer, what about other women in the family? If they are offered testing for the same biomarkers, the doctors could head off big trouble by catching any cancer early. Likewise, there are 94 million ex-smokers in the U.S., meaning they have elevated cancer risk. Subjecting each of them to an annual CT scan would catch early-stage lung cancers and reduce mortality from the disease by perhaps 20%. Given that there are 175,000 new lung cancers diagnosed every year, that’s a lot of lives. But getting all those people into a CT machine is neither practical nor even possible. Instead, MD Anderson is developing a simple blood test for a protein marker that could, when used in combination with diagnostic imaging and risk models, detect lung cancer earlier than it is typically found.
Team science isn’t appropriate for every aspect of cancer research. Nor is it issue-free. One question up for grabs: How long should a team be together? SU2C’s initial funding is for three years, although some teams have secured money for additional years. The pancreatic team, for instance, just received two grants of $2 million each from the Lustgarten Foundation and SU2C for another two years of work. At MD Anderson, DePinho is committed to the team concept, but he’s also willing to defund or change the leadership of teams that don’t perform. The state of Texas, following the team model, passed a $3 billion bond issue to fund cancer research, but the program has been plagued by allegations of political intrigue and mismanagement.
The traditional researcher, sitting alone or with a couple of postdocs in a lab somewhere, working on that eureka moment, will always have a niche in this new ecosystem. “We still need people looking under rocks,” says Dr. William Nelson, director of the Johns Hopkins Cancer Center, a vice chairman of SU2C’s scientific-advisory committee and a successful rock looker underer, having discovered the most common genome alteration in prostate cancer. But the shift to team science is permanent. When he first considered SU2C’s team structure, Drebin was skeptical. “My feeling was that this was naiveté on the part of Hollywood executives,” he says. “You can make a movie this way. But not science. I take that back.”
It’s a new script for an old plot, and there is still a lot to be written as researchers learn more about the mutations driving most cancers. All we need now is the Hollywood ending.
With reporting by Alice Park