The Longest War

TO: Mick Jagger, Barry Manilow, Joe Namath, Al and Tipper Gore, Tuesday Weld, and the other nearly 3 million Americans turning 65 this year

FROM: The Baby Boomers

Happy birthday, everyone. (To be frank, the rest of us weren’t sure all of you would make it this far.)

Now more than ever, it’s important to look after your health. Had a fecal occult blood test lately? How about that colonoscopy? You are keeping up with those annual mammograms and prostate exams, aren’t you? Please don’t put them off—in the future, it may be harder to get in to see your doctor.

In less than three years, the first wave of baby boomers will hit 65—the age at which cancer incidence and mortality start to climb. The largest population bulge in America’s history is about to hit the health-care system like a freight train loaded with junk food.

For all cancers combined, the incidence of cancer is 10 times greater for people 65 or older. And older cancer patients are 16 times more likely to die from the disease than their younger counterparts.

By the time the last baby boomers reach 65 in 2030, the number of individuals in the United States who are that age and older is expected to double, from about 35 million to 70 million. By then, the group that is 85 and older is projected to reach about 9.6 million, more than double the number in that age range at the turn of the century. All this signals a runaway cancer hit barreling down the tracks, with twice as many people expected to get that diagnosis—about 2.6 million—by 2050.

Even though the individual cancer rate has remained stable since the early 1990s, the big boomer group will push up the nation’s overall cancer burden as they move into old age. Observers worry about a range of issues, including whether we’ll have enough oncologists (more than half the country’s oncologists are over age 50) and other specialists to treat them and whether patients will be able to pay for care.

“Tennessee is one of seven contiguous states with the highest cancer death rates. Until those outcomes change significantly, our jobs are not done.”

~ Jennifer Pietenpol, director, Vanderbilt-Ingram Cancer Center

Older cancer patients often suffer from one or more chronic conditions, with hypertension, arthritis and heart disease leading the list. These co-morbidities make treating cancer more complicated.

And while older patients in the United States aren’t excluded from clinical trials based solely on age, they don’t participate in great numbers. This means the learning curve may be steeper for managing the side effects of new cancer drugs and therapies for older patients.

“I think the bright side is that we are making continual inroads into our understanding of cancer and how cancer comes about in the first place,” says Vanderbilt-Ingram’s deputy director, Dr. David H. Johnson, past president of the American Society of Clinical Oncology.

Recent research breakthroughs hold the promise of great progress toward understanding the basic biology of cancer and devising treatment approaches that will manage it for a lifetime or perhaps even prevent it altogether.

The sequencing of the 20,000 or so human genes already has improved our understanding of the genetic “switches” that turn on tumors. One benefit: discovery of new compounds that can switch off malignant growth without harming normal cells. Also on the horizon: screening blood tests that harness the power of proteomic “fingerprints” to detect early cancer, even before symptoms occur (see sidebar article).

“The cancer field has made great progress,” says Jennifer Pietenpol, who in January was named director of the Vanderbilt-Ingram Cancer Center. “The decline in cancer deaths across the country continues. That’s good news, but we still have a lot to do.”

Pietenpol, who is also the B.F. Byrd Jr. Professor of Oncology and a professor of biochemistry, was named to head the VICC after having served as interim director following the departure of Dr. Ray BuBois, who in 2007 left Vanderbilt to become provost and executive vice president of the M.D. Anderson Cancer Center in Houston.

Vanderbilt-Ingram Cancer Center by the Numbers

4,000—approximate number of new cancer patients each year
65,000—outpatient visits annually
300—approximate number of cancer investigators in 7 research programs
7th—ranking in competitively awarded National Cancer Institute grant support
$150 million+ in annual research funding
One of 41 National Cancer Institute-designated Comprehensive Cancer Centers nationwide
One of 21 leading centers worldwide in the National Comprehensive Cancer Network

Pietenpol received her doctoral degree in cell biology from Vanderbilt in 1990, followed by a postdoctoral fellowship in oncology at Johns Hopkins University. In 1994 she joined the Vanderbilt faculty and soon after received a Burroughs Wellcome Fund Award for her research in cancer biology and toxicology.

Whether in conversation or in formal presentations, Pietenpol speaks clearly about the center’s overarching purpose—to eliminate death and suffering from cancer, for individual patients by delivering first-rate, evidence-based care, and on a global scale through its innovative science and translational research.

“Our goal is not to be one of many centers or hospitals doing the same thing,” Pietenpol says. “It’s to be at the cutting edge of research and clinical care and to set the example. I am very optimistic about our future.”

She has assumed leadership of VICC at a pivotal point in the growth and development of Vanderbilt-Ingram, which in only its second decade has established itself as one of the nation’s premier cancer research institutions and as the region’s leader in consumer preference for cancer care.

Nationwide, the National Cancer Institute has named 41 centers as Comprehensive Cancer Centers, a designation given to leaders in research, treatment, education and outreach. VICC is the only care center in Tennessee that conducts research and provides treatment in all cancers among adults and children, and one of just a handful in the Southeast.

“If you consider winning the war on cancer to be understanding the molecular basis of the disease, then we’ve made, and are making, huge strides,” Pietenpol says. “From a patient’s perspective, success means being diagnosed when you can be cured and when screening tools are available for early detection of recurrence or second cancers for years to come. That’s where we want to focus our resources. The clinical and basic research has built our reputation, and while it is expensive, it’s our most important investment.”

Over the past two years, Pietenpol has overseen a $15 million expansion that will double the capacity of the cancer outpatient clinic and chemotherapy infusion center.

Vanderbilt-Ingram’s focus is on areas that will have the greatest impact on future generations, including early detection and prevention; identification and validation of new molecular targets for therapy; design and initiation of high-impact clinical trials; development of “personalized” cancer treatment; and provision of the most innovative, compassionate care for patients, families and long-term cancer survivors.

“To this day, if there were a trial I were a candidate for, I’d be the first one to raise my hand because I’ve seen so much good come from these trials.”

~ Breast cancer survivor Teresa Lundberg, who believes participation in Vanderbilt-Ingram Cancer Center trials of the drug Herceptin helped save her life

This emphasis on patient care, in particular, marks the recent evolution of VICC’s mission. “We have a commitment to provide excellent care to patients, regardless, but more patients also means more candidates for clinical trials, more tissue samples for research,” notes Pietenpol. “All of that increases, as does the opportunity for clinicians to provide feedback to fuel our discoveries in the lab. It’s synergistic.”

Tropic of Cancer

Before a discovery in the laboratory can become a treatment available to millions of patients, it must go through rigorous clinical trials. Among the Vanderbilt-Ingram Cancer Center’s achievements is its role in innovative, investigator-initiated trials with the greatest impact for patients.

And Vanderbilt has plenty of research subjects in its own backyard. Researchers have their own name for the Southern region of the United States—the Cancer Belt.

“When you look at a map of brain cancer incidence in the United States, the Southeast just lights up in red,” says Dr. Reid Thompson, associate professor and vice chairman of the Department of Neurological Surgery. Thompson and co-investigator Kathleen Egan are participating in a study to find clues that may explain this brain cancer cluster. (Egan, formerly of Vanderbilt-Ingram Cancer Center, is now on faculty at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla.)

Vanderbilt-Ingram, along with four other cancer centers in the region, will enroll as many as 1,000 patients in the federally funded initiative. “We’re asking patients about their diets, possible job-related exposure to cancer-causing chemicals, and we’re collecting DNA samples,” explains Thompson, who also serves as director of Vanderbilt’s Brain Tumor Center. “We know some genetic markers are linked to other forms of cancer, and they may play a role in brain cancer as well.”

Brain cancer isn’t the only cancer taking a disproportionate toll on Southern populations. Topping the list is lung cancer. Southerners smoke more than people in other regions and are far more likely to be diagnosed with lung cancer. Cancers of the mouth and throat, also linked to tobacco use, are more prevalent in Southern states, too. “Instead of cigarettes, it is the use of snuff and chewing tobacco—among women as well as men—that causes this spike in oral cancers,” says William Blot, professor of medicine.

Behavior like tobacco use is clearly linked to some forms of cancer. But it is less easy to explain why people living in the South are developing many types of cancer at higher rates. And it doesn’t explain why African-Americans are more likely to develop and die from some cancers.

“When you start getting up in numbers of people with a particular type of cancer that approaches 1,000, that gives you a pretty good power to start looking at environmental and genetic factors.”

~ William Blot, principal investigator, Southern Community Cohort Study

Blot leads the Southern Community Cohort Study (SCCS), the largest epidemiologic study in history, to explore why the South has become the Cancer Belt and why African-Americans experience higher rates of many types of cancer. Starting with a $28 million grant from the National Cancer Institute, the SCCS hopes to recruit 90,000 people in 12 Southern states to learn about their lifestyles, their medical histories, and their risk factors for cancer and other serious diseases. Two-thirds of the participants will be African-American, and many will be from rural areas.

The SCCS is a collaborative project among Vanderbilt-Ingram, Meharry Medical College, and the International Epidemiology Institute, as well as participating community health centers across the South. SCCS researchers rely on community health centers to enroll study participants, most of whom are low-income individuals.

“The study participants form one of the groups at highest risk for cancer that has ever been studied,” says Blot. “Most other investigations have not included large numbers of African-Americans, and few have included low-income individuals and people from rural parts of the country. This is the first large-scale study and the first in the South to include large numbers of all those groups.”

Even when the incidence of a form of cancer is higher among whites, the survival rate is nearly always lower for blacks. The reasons are not clear, but suspected culprits include differences in access to screening or treatment, stage at diagnosis and aggressiveness of disease.

Breast cancer is a good example of this anomaly. While white women in states like Tennessee are slightly more likely to be diagnosed with breast cancer than African-Americans, African-American women are far more likely to die from the disease.

“We do know that a significant lifestyle component is linked to cancer incidence,” says Bettina Beech, associate director of health disparities research for Vanderbilt-Ingram. “If we increase fruit and vegetable consumption, decrease fat consumption and increase physical activity, we can avoid a huge percentage of cancer cases. But it is not that simple for people living in some areas. For low-income individuals, regardless of whether they are minorities, there is reduced access to grocery stores with high-quality produce in many neighborhoods.”

While lifestyle factors and access to preventive surveillance and treatment play a role in cancer, scientists increasingly are finding genetic differences that may explain some of the disparities. African-American men are far more likely to be diagnosed with prostate cancer than white men, and more than twice as likely to die from the disease. Researchers have discovered a combination of genes that appears to play a role in the aggressive forms of the disease often found among black men.

“If we increase fruit and vegetable consumption, decrease fat consumption and increase physical activity, we can avoid a huge percentage of cancer cases.”

~ Bettina Beech, associate director of health disparities research

“It’s been speculated for a number of years that vitamin D may play a protective role in cancer,” Blot says. “Researchers have found lower blood levels of vitamin D among people living at northern latitudes, and those populations are more likely to develop certain forms of cancer. Because we know that exposure to sunlight helps the body produce vitamin D, it stands to reason that someone with dark skin may not be getting enough of the vitamin. Our study in the South found roughly half of the African-American population had insufficient levels of vitamin D versus only 10 to 15 percent of the white population.”

If researchers can determine exactly how vitamin D influences cancer risk, they may be able to supplement the diets of those who have insufficient levels of the vitamin.

Nutritional factors are thought to play a role in the etiology of more than one-third of all human cancers, yet information about the preventive potential of specific dietary compounds is scanty. But one study offers unique opportunities to fill such knowledge gaps.

Door to Door in Shanghai

Half a world away from the fast food and barbecue-laden tables of the American South, Dr. Wei Zheng earned a medical degree and master’s degree in public health at Shanghai Medical University, where he also met his wife and colleague, Xiao Ou Shu. Nearly 20 years ago they immigrated to the United States for Ph.D. training at Johns Hopkins University and Columbia University, respectively.

Zheng was involved with the Iowa Women’s Health Study while working at the University of Minnesota, writing a paper focusing on consumption and cancer risk, when it struck him: “Most studies look at what is bad about diet. I thought, We need to focus on what is good about diets to help protect against cancer,” Zheng says.

And so began the Shanghai Women’s Health Study, which has yielded important clues to the mysterious connections between environment, genetics and disease. Funded since 1996, the study includes 75,049 Chinese women who were between the ages of 40 and 70 at the time of enrollment between 1997 and 2000 and who lived in urban Shanghai, where intake levels of many hypothesized cancer-inhibitory dietary factors are high and diverse. The primary focus of the research is to determine whether certain diets—those with high intakes of folate, soy foods, allium vegetables, crucifers and tea—are associated with a reduced risk of cancer.

The Shanghai investigation is known as an epidemiologic “cohort” study. It is designed to track the development of disease in a large group of people over an extended period of time—usually decades. Cohort studies can help reveal the impact that diet, exercise and other lifestyle factors can have on health and longevity.

While working with her husband on this study, Xiao Ou Shu realized that more could be gained than by simply studying women. In 2001 she launched the Shanghai Men’s Health Study. To date, 60,000 men have been enrolled, half of whom are married to participants in the women’s cohort.

“First we did a small pilot study and discovered that the husbands’ and wives’ dietary habits are very different, although they share the same living environment,” Shu says. “For instance, men like to eat more meat compared to the women.”

The studies rely on trained interviewers who go door to door. Because most Shanghai residents live in apartment towers, dozens of study participants can be found in one building.

“Sometimes the associations between lifestyle and disease are so striking it surprises us.”

~ Dr. Wei Zheng, director of the Vanderbilt Epidemiology Center, with Dr. Xiao Ou Shu, epidemiologist and professor of medicine

One goal of the Shanghai and Southern Community cohort studies is to determine whether differences in traditional Asian and Western diets account for widely varying incidences of different cancers among residents of China and the United States. Researchers know that Asia and the United States have quite different cancer spectra. In China and Japan, stomach cancer used to be the No. 1 culprit, followed by cancer of the esophagus, whereas in the United States, lung, colon and breast cancers dominate.

However, the cancer spectrum in some parts of China, such as Shanghai, is starting to more closely resemble that of the United States. For people who move from China to the United States, the risk of stomach and esophageal cancers decreases while the risk of lung, colon and breast cancers dramatically increases.

The Shanghai Women’s Study already has begun to shed light on a number of areas. “Sometimes the associations between lifestyle and disease are so striking it surprises us,” says Wei Zheng.

Among the findings: “Women who are nonsmokers but who are exposed to the cigarette smoking of their husbands have an increased risk of dying of stroke,” Zheng says. “We also learned that soy-food intake reduces the risk of fractures, hypertension, coronary heart disease and diabetes.”

Simply adopting Asian eating habits may not yield the same benefits in the United States. “Even though lots of people in the South eat rice and greens, as do people in Shanghai,” Shu says, “the specific type of vegetables and the way the food is prepared is very different.”

Both the Shanghai studies and the Southern Cohort Study track participants by name, address, Social Security number and, in Shanghai, by citizenship ID number. Researchers regularly monitor government registries in China and the U.S. that track disease and deaths reported by health officials. Participants also are contacted periodically to update their disease and exposure information.

Biological samples—urine, blood, cheek cells (for DNA)—are sent to Vanderbilt University Medical Center, where they are stored in freezers for future analysis.

“We need to understand why people are at increased risk, to be the ones leading early detection and diagnosis, to use our research capabilities to offer the best treatments with the least side effects,” says Pietenpol. “That’s the position of this cancer center—to understand the molecular basis well enough to detect cancer early and to offer the most streamlined, individualized, multidisciplinary care.”

Shotgun Proteomics

Will fingerprinting cancer lead to its arrest? That’s the hope of proteomics, the science of proteins.

Researchers are trying to identify patterns of proteins in blood and tissue samples that reflect the presence of diseases like cancer in the body. These patterns, often called “molecular fingerprints,” could serve as biomarkers for early detection. By improving early detection, biomarkers could increase the chances for successful treatment and survival—from risk assessment to early detection to prognosis to therapeutic response and disease recurrence.

Currently, though, there is a lack of standardization of techniques used to analyze proteins. As a result, “the overall reliability of the approach is not currently sufficient to apply it directly to clinical research,” says Daniel C. Liebler, director of the proteomics laboratory in the Vanderbilt Mass Spectrometry Research Center.

Liebler is heading up one of five teams across the country to standardize proteomic technologies and move them forward. The project is part of the National Cancer Institute’s Clinical Proteomics Technologies Initiative. Richard Caprioli, co-director of the Vanderbilt team, directs the Mass Spectrometry Research Center and has helped pioneer the technology used to identify and analyze protein biomarkers in tissue samples.

“Many of the differences among proteins in disease states and in normal health are not differences in the amounts of the proteins themselves, but in the modified forms of proteins that are present,” explains Liebler, who is a professor of biochemistry, pharmacology and biomedical informatics. Abnormal genes, for example, may encode abnormal proteins which, in turn, trigger a cascade of events leading to cancer.

“Proteins are commonly dressed up in many different kinds of modifications that control their activity and function,” he says. “The problem lies not so much in identifying the proteins, but in ‘frisking’ them—being able to detect differences in modified protein forms.”

Vanderbilt’s approach to frisking is called “shotgun proteomics,” in which proteins from a biological sample are cut into small pieces called peptides, analyzed using mass spectrometry techniques, and then put back together.

“Everybody has their own way of doing shotgun analysis,” says Liebler, adding that his team’s goal is to standardize the technology.

The standardization effort mirrors approaches being developed for early detection of colorectal cancer in the Jim Ayers Institute for Precancer Detection and Diagnosis. Liebler also directs this institute, part of the Vanderbilt-Ingram Cancer Center. The Jim Ayers Institute was established at Vanderbilt-Ingram in 2005 with a five-year, $10 million gift from its namesake. One goal of the institute is to identify new markers to detect colorectal cancer at its earliest stages using new proteomics technologies developed at Vanderbilt.

Other Vanderbilt researchers have found proteomic “signatures” that potentially may improve the early diagnosis and treatment of lung cancer, and they are scanning protein profiles found in the blood of African-American and Caucasian women for clues to why African-Americans die more frequently from breast cancer.

~ Bill Snyder

Find out more online.

More than one-third of Vanderbilt University Medical Center’s funding from the National Institutes of Health is cancer based. Traditionally, the federal government has led the charge in the war on cancer and other public health efforts by funneling dollars through national agencies like the Centers for Disease Control and Prevention and the National Institutes of Health. But federal funding to fight cancer, which will directly impact one in three Americans, has stalled. And the NIH-funding slice for the National Cancer Institute—the nation’s principal agency for cancer research—is expected to continue to decline.

“We’ve remained remarkably competitive for large collaborative grants, even in these tight times,” Pietenpol says. “For example, on the last four major grants for which we’ve competed, we not only received outstanding scores but the top scores in the nation. Yet we must be even more competitive for even tighter resources.

“Top-shelf research and quality care are very expensive,” she continues. “Our progress, to some extent, will be dictated by how much money is available. If we want to continue our momentum, we must be as competitive, if not more so, for the extramural funds that are available—in federal dollars, foundation support and private donations.

The progress in understanding cancer at the molecular level is due to what Pietenpol calls “mind-boggling” advances in technology, informatics, and the pace of scientific discovery in the past 20 years.

“A generation ago it was one scientist investigating one gene or pathway—or maybe pathways limited to one or two proteins,” Pietenpol says. “Today it’s not unusual for one scientist to study hundreds of proteins, thousands of genes, in collaboration with colleagues all over the world.”

“At the same time we are finally starting to make strides in curing some forms of cancer, the federal government has put a lid on research dollars. With inflation, that means we’re actually losing money crucial for research.”

~ Dr. David Johnson, cancer survivor and deputy director of Vanderbilt-Ingram Cancer Center

No one involved in the struggle to solve cancer’s riddles is underestimating the challenge, however. Cancer is an old and wily adversary, going back at least as far as the dinosaurs—evidence of malignancies has been found in fossils dating back 80 million years.

“Yes, cancer deaths are declining, but one in every two men and one in every three women will have cancer,” Pietepol says. “Tennessee is one of seven contiguous states with the highest cancer death rates. As a Comprehensive Cancer Center located right in the middle of these states, it is our obligation to focus our work where we can make the most impact. Until those outcomes change significantly, our jobs are not done.”

What keeps Pietenpol and Vanderbilt’s 300 other cancer investigators optimistic is part scientist’s curiosity and part pride in the team of professionals around them. “It’s the clinical enterprise, the investigators involved in treating patients with cancer,” says Pietenpol. “It’s the clinical, basic, translational and population-based research aimed at cancer. It’s the people who do the valet services for our patients. It’s the people doing the most complicated surgical resection.”

Not long before she became the VICC’s interim director in 2007, Pietenpol recalls, a childhood friend died of renal cancer. “She was diagnosed right after Labor Day and died the week after Thanksgiving—90 days from diagnosis to death. She was 40, and died three days shy of her daughter’s first birthday. So this is personal, and the older I get, it seems to get more personal every day. We must pick up the pace.

“I know far too many people who have suffered from cancer. It’s what’s always propelled me. When you’re involved in cancer research, cancer treatment and cancer education, everything you do, you’re doing for a reason.”

Cynthia Manley, Dagny Stuart, Elizabeth Older, Bill Snyder, Heather Newman, Stephen Doster and GayNelle Doll contributed to this story.