Research Magazine 2010
About half of all men and one third of all women in the United States will get cancer at some point in their lives. The disease kills more than half a million Americans every year, and within two decades it will surpass heart disease as the nation’s leading cause of death, according to the American Cancer Society. Boston University researchers are attacking this disease on many fronts—spreading the word on risk and prevention, finding innovative ways to increase the effectiveness of established therapies, training the next generation of cancer fighters, uncovering new drug targets, and enlisting the body’s immune system as an anti-cancer warrior.
Cracking the Cancer Code
Is some disease risk riskier than the rest?
Last May, under pressure from the Food and Drug Administration, Walgreens postponed its plans to sell a test that claimed to show genetic risk for cancer and other diseases. These types of direct-to-consumer genetic tests worry many public health experts, including Catharine Wang, an assistant professor of community health sciences in the School of Public Health. Wang studies how the public interprets and acts on disease risk—or doesn’t. Much of her recent work has focused on how people understand genetic cancer risk.
Wang believes that direct-to-consumer tests give people an incomplete sense of their cancer risk, which may cloud public health messages about health behaviors—such as eating right, exercise, and routine physicals and screenings—that are known to reduce the onset and lethality of the disease. She notes that an individual’s chance of contracting any disease typically involves a complicated interplay of genetics and lifestyle choices, with a lot of unknowns.
“ There are a lot of people saying, ‘I’m smart enough to make decisions; give me the information and get the doctors out of the way.’ But they’re making some serious decisions about their health after seeing only part of the picture.”
“Every day, there are more findings of genetic associations from minor DNA variants, and industry jumps on those discoveries,” she says. “But the public health community is saying, we’re not ready.”
Some of the open questions include whether people will overestimate risk when it stems from their genes and whether knowing something about their genetic predispositions will make them more or less likely to make the health behavior choices that reduce disease risk.
In a study published last year in the journal Cancer Causes and Control, Wang found that the vast majority of more than 400 healthy women who were surveyed ranked heredity as the most important causal factor for both breast and colon cancer—84 and 78 percent respectively, despite the fact that prior studies have estimated that 38 percent of breast cancers and 45 percent of colon cancers are preventable through a combination of healthy eating, exercise, and weight management.
Suzanne Miller, director of the psychosocial and behavioral medicine program at the Fox Chase Cancer Center in Philadelphia and one of Wang’s research collaborators, says, “As we learn more and more about cancer and its treatment at the genetic level, Catharine’s work shows us that we need to intervene at the level of the whole person, not just at the level of their molecular genetics.”
What is needed now, says Wang, is an understanding of what genetic risk information will motivate people to choose healthy behaviors and what risk information, if any, might actually impede these healthier lifestyle choices. For example, a “high” genetic risk could scare some people into fatalism, while a “low” genetic risk might give others a false sense of security. She says that the “rush to market” of direct-to-consumer genetic tests ignores these basic questions about genetic risk interpretation and behavior that public health researchers are only starting to answer.
“There are a lot of people saying, ‘I’m smart enough to make decisions; give me the information and get the doctors out of the way,’” says Wang. “But they’re making some serious decisions about their health after seeing only part of the picture.”
Tracking a Killer
Image courtesy of Muhammad Zaman
Muhammad Zaman’s fight against brain cancer in kids began with a wrong turn. A few years ago, while searching for a colleague’s lab in the University of Texas’s M.D. Anderson Cancer Center, he got lost and ended up in the pediatric ward.
“My daughter had recently been born, and it pained me to see how many of these kids were probably not going to make it,” says Zaman, an assistant professor of biomedical engineering.
Zaman had been seeking a clinical application for his research into the physical, chemical, and biological details of cancer cell migration in the body, what’s known as metastasis. Partnering with researchers at the Massachusetts Institute of Technology and the University of Manchester (UK), he decided to focus on pediatric brain cancer, which gets much less research attention than the most common childhood cancer, leukemia. Zaman’s goal is to use his intricate computational and experimental models of pediatric brain cancer cell migration to pinpoint the key biochemical mechanisms that support metastasis.
Traditionally, he says, clinicians followed a “Mini-Me strategy” when it came to treating cancer in kids, simply cutting the dose of the same chemotherapy drugs used for adults. But children’s rapid development means that the environment in which cancer grows and migrates in their bodies is far different than it is in adults.
In addition, one of the major reasons why so many chemotherapy drugs fail when transitioning from the lab to the clinic, Zaman says, is that they are developed by watching cancer cells move on two-dimensional plastic surfaces. The key for more successful drug development, therefore, is to study cancer cell migration and test therapeutics using a more lifelike model of a biological system.
“It’s not about looking at a single gene in isolation. It’s about how genes and the environment interact, how one protein influences another, and how those interact with the cellular systems and with the structures inside the body.”
Supported by nearly $2 million in funding from the National Institutes of Health, Zaman and his research partners use a laser-scanning microscope to track cultured cancer cells moving through three-dimensional “matrices” of a common protein such as collagen, or a synthetic soft-tissue. They then assemble the time-lapse microscopic images into detailed computer simulations of real-time cell movement.
“This is what the cells see as they travel through the matrix,” says Zaman, as he plays one such video on his computer; it shows a tunneling journey through the amorphous network of a porous protein structure. The experiments are used in combination with computational models Zaman has built from what is already known about cell signaling and cell binding, and about the stresses and the forces operating within the matrix. He periodically refines and improves the models based on experimental data.
“We’re trying to find out what enables or hinders cancer cell migration and invasion, so that people will be able to develop therapeutics that specifically target those mechanisms,” says Dewi Harjanto, a biomedical engineering doctoral student who works with Zaman.
While most studies look at individual cancer cell migration, Harjanto is investigating how clusters of cancer cells, mini-tumors, sometimes migrate away from the main tumor. She is focusing on how the density of the collagen matrix affects this movement.
Another collaborator, Roger Kamm, an MIT professor of mechanical and biological engineering, is using microfluidic systems to see how cancer cell movement is affected by varying the fluid flow through the matrix. Other experiments alter the pH of the matrix or the DNA of the cancer cell. Eventually, says Zaman, they will introduce different drugs to these systems, “to see what happens to those cells and their ability to move, divide, and form tumors.”
No matter what variable is being altered, “this is a systems question,” Zaman stresses. “It is not about looking at a single gene in isolation,” he says. “Instead, it’s about how multiple proteins inside the cell interact with the environment of the tumor, how one protein influences another, and how those interact with the cellular systems and with the structures inside the body.”
Engineering a New Line of Defense
Image from Corbis Images
Part of what makes cancer so deadly is subterfuge—even while it invades and destroys the body’s organs, most cancers appear “normal” to our immune system’s T-cells, a type of white blood cell and the core of our defense against disease.
But the jig may soon be up for some cancers, thanks to Richard Junghans, an associate professor of surgery and an oncologist and hematologist at the BU-affiliated Roger Williams Medical Center in Providence, Rhode Island. Funded by a 2009 $5.9 million Impact Award from the Department of Defense’s Breast Cancer Research Program, Junghans is genetically modifying T-cells to recognize cancer cells and kill them.
“These are living drugs, made from the patient’s own cells,” says Junghans, who is currently overseeing Phase I clinical trials of the designer T-cells—which he affectionately calls “nano-bio-bots”—to fight metastatic breast cancer. “Using the immune system is the fourth arm of cancer therapy with the hope of succeeding even when we have a patient whose cancer is growing despite chemotherapy, radiation, and surgery,” he says.
Cancer patients travel to Roger Williams from around the country to receive treatment in the clinical trials. At the Roger Williams Cancer Center, in a building adjacent to Junghans’s office, T-cells are harvested from the patients’ blood. Downstairs, in a cleanroom, researchers use a genetically engineered virus that cannot reproduce to carry a bit of new genetic code into the T-cell chromosomes, programming a new receptor to recognize a signature molecule, known as carcinoembryonic antigen, or CEA for short, that is present in half of all breast cancers.
These genetically modified T-cells are cultured until about 400 billion are grown per patient. Then, they’re infused through an IV back into the patients in varying amounts, after which patients are observed over several weeks as outpatients. The current trials are using a “second generation” of designer T-cells. The first generation was tested about a decade ago. They were effective in killing cancer cells, but didn’t keep at it for long, because not only do T-cells need to be educated about what to attack, they also need to be activated by signals from other cells in the immune system, called dendritic cells. Junghans’s second-generation T-cells have a special signaling chain—engineered to activate when the T-cells encounter a tumor—built in along with the CEA receptor. This signaling chain should allow the T-cells “to proliferate, and survive, and maintain their active status,” he explains.
Because CEA is also expressed by some healthy tissues, the Phase I trials are using “escalating exposures” to the new T-cells in order to identify what Junghans calls “a window of therapeutic opportunity between anti-tumor effectiveness and patient toxicity.”
The Phase I trials will continue for another year, and Junghans’s research team is continuing to make small modifications to the designer T-cells. Phase II and III clinical trials will follow, with the goal, Junghans says, of curing breast cancer that expresses CEA within the next five years.
When it comes to killing cancer, sometimes timing is everything. In studies backed by the National Institutes of Health, David Waxman—who is a professor of biology and a professor of medicine, as well as associate director for basic research at the BU Cancer Center—has found that simply altering the scheduling of chemotherapy may enlist the body’s immune system as an additional cancer fighter.
Waxman’s research builds on the idea of “metronomic chemotherapy,” conceived about a decade ago by the late Judah Folkman, the famous cancer researcher of Children’s Hospital Boston. Instead of giving patients several, widely spaced rounds of a “maximum tolerated dose” of chemotherapy, which poisons both cancerous and healthy tissue, Folkman proposed using lower chemotherapy doses more frequently. In his studies, metronomic chemotherapy not only killed cancer directly through toxicity, it also shrank tumors. The theory on the latter effect was that more frequent drug doses did sustained damage to the blood vessels that supply tumors with oxygen and nutrients, a process known as “anti-angiogenesis.”
In Waxman’s own metronomic chemotherapy studies, which involved administering an older drug called cyclophosphamide every six days to mice with induced tumors, he observed tumor regression to an extent “that we had never seen using maximum tolerated dose.” Some tumors even disappeared completely.
But, says Waxman, “we reasoned that there had to be another mechanism,” beyond destroying blood vessels. They based this suspicion partly on the relatively weak tumor-shrinking performance of a new class of anti-cancer drugs that specifically work as anti-angiogenesis therapies, targeting the tumor-feeding blood vessels.
And they were right. When Waxman and his team compared some of the new, anti-angiogenesis drugs directly with metronomic chemotherapy, the anti-angiogenesis drugs were better at knocking out blood vessels, but not nearly as effective in actually shrinking the tumors. In addition, says Waxman, studies carried out by Joshua Doloff, a doctoral student in Waxman’s lab who graduated this May, revealed “lots of immune cells populating the tumors” of the mice receiving metronomic chemotherapy. That raised the astounding possibility that an older chemotherapy drug not only outperforms a new drug specifically designed to starve tumors of their blood supply, but that this older drug was recruiting a cancer fighter that researchers have been trying to harness for years—the body’s innate immune system.
Unlike the adaptive immune system, which attacks only specific pathogens it identifies as foreign, the innate immune system is a more general defense against infection. Waxman and his collaborators are now trying to determine why metronomic chemotherapy might trigger this response. One hypothesis favored by Doloff is that the repeated damage to cells by metronomic chemotherapy triggers a sustained inflammation response. “In that case,” says Doloff, “the immune system is going in basically to clean up the mess.”
The mystery is complicated by the fact that the treatments are remarkably effective against some tumor types but relatively ineffective in shrinking others, including some types of colon, lung, and prostate tumors. “We need to understand more about the mechanism to know whether there’s a way to stimulate this process in humans,” says Waxman.
Knowing the Enemy
Behind the 1.4 million new cancer cases in America every year are even more stories—about lives before and after the diagnosis and about the ups and downs of treatment. Last April, second-year Boston University School of Medicine students heard one of these stories from a 67-year-old woman who recently completed surgery and radiation for breast cancer.
The students listened, and then they asked questions ranging from, “How did you first react to the diagnosis?” to “Is it okay for oncologists to hug their patients?”
“Cancer is the second leading cause of death in this country, and rising. And about 60 percent of cancer patients will be treated with radiation. We need to make sure we’re as prepared as we can be for that.”
The class is part of the Oncology Education Initiative, spearheaded by Ariel Hirsch, an assistant professor of radiology,and Karen Antman, dean of the School of Medicine.
“No matter what field they choose, every medical student is going to encounter cancer at some point in their career,” says Hirsch, whose education initiative began in 2007 when she arranged to give a single lecture on radiation oncology to all fourth-year medical students during the core radiology rotation.
In 2009, her efforts were helped by an education grant from the Radiological Society of North America, and she became the leader of a new two-week oncology block in the medical school’s second-year curriculum. Previously, BU medical students learned about cancer in a piecemeal fashion— covering lung cancer in the pulmonary block and colon cancer when learning about the gastrointestinal system, for instance. In addition, the fourth-year rotation in radiology was expanded to third-year students, giving more students the chance to shadow Hirsch as she treats patients and to collaborate in her research.
Such comprehensive cancer education, particularly the instruction in radiation oncology, is rare in medical schools, says Hirsch. In fact, a 2009 literature review found only seven journal articles in ten years that mentioned teaching radiation oncology to medical students, and two of them were about the efforts at Boston University.
“Cancer is the second leading cause of death in this country, and rising. And about 60 percent of cancer patients will be treated with radiation,” says Hirsch. “We need to make sure we’re as prepared as we can be for that.”
Being prepared includes understanding the emotional side of patient care, says Hirsch, whose office is decorated with gifts from former patients—a doll from Trinidad, a decorative plate adorned with a Jamaican flag, a wood figurine carved by a Haitian patient.
It also means learning about the cutting-edge radiation equipment that sits behind thick, shielded doors down the hallway from Hirsch’s office, such as the “CyberKnife,” installed in 2008, which uses a large, robotic arm to deliver a high dose of radiation from multiple angles, and has image-guided tracking software and a camera that syncs the radiation beam to a patient’s breathing cycle for increased accuracy.
Finally, it means exposure to research. Hirsch invites students to collaborate with her in ongoing studies, on topics such as radiation therapy after robot-assisted prostate cancer surgery, and the effects of embedding radiation-emitting radioisotopes in the cement used to reinforce vertebrae and alleviate the pain of malignant compression fractures that result from cancer spreading to the spinal column.
Hirsch also involves students in measuring the effectiveness of the oncology education initiative and in finding ways to improve and expand it, with the ultimate aim, she says, of creating a model for oncology education at other medical schools. One of Hirsch’s advisees, Nick DeNunzio, who is pursuing a joint MD/PhD in physiology and biophysics, is the lead author on a paper recently accepted by the Journal of the American College of Radiology. It recommends that medical schools reinforce oncology education with extracurricular initiatives such as lunch-time faculty seminars, student interest group advising, mentoring programs, and summer research internships.
“It’s these auxiliary pieces of education, not necessarily in the classroom, that can supplement and strengthen an understanding of the field,” says DeNunzio. After all, he says, “you only have so many hours in a day, and you have all of medicine to cover during those four years.”