A Different Kind of Chemo
Chemopreventive agents in the news have included tamoxifen, a substance derived from yew trees that can reduce the risk of breast cancer, and broccoli sprouts, which contain a compound that promotes production of enzymes that prevent harm to DNA.
You places his laboratory halfway along the chain of development from lead to treatment. He doesn’t screen dozens of potential chemopreventives—“they’re about 90 percent wrong and 10 percent gold,” he says— but instead tests the best leads in animals and isolates the compounds providing the chemopreventive effect.
A NEW APPROACH TO THE WAR ON CANCER has caught the interest of a growing group of scientists: Increase consumption of compounds that reduce genetic damage and other cancer-promoting processes, and patients can decrease the chance that tumors will ever develop.
The strategy, known as chemoprevention, is only about 20 years old. New leads for chemoprevention treatments sometimes come from traditional medicine, so it’s easy to confuse chemoprevention with the vague promises of better health attached for centuries to maternal calls of “Eat your vegetables!”
Ming You, MD, PhD, professor of surgery, is determined to convince both the general public and other faculty members at the School of Medicine that not only is chemoprevention a hard science, it’s a field in which the potential benefits are well worth pursuing.
“This is a far cry from people saying, ‘If you just eat healthy, you maybe will have less disease for the next 20 years,’” You says. “It’s a new idea that these kinds of dietary alterations can have quantifiable medical effects, but they lead to predictable outcomes. You can actually calculate how many cancer cases you can cut per hospital.”
CHEMOPREVENTIVE AGENTS IN THE NEWS have included tamoxifen, a substance derived from yew trees that can reduce the risk of breast cancer, and broccoli sprouts, which contain a compound that promotes production of enzymes that prevent harm to DNA.
You thinks that Washington University has the resources to make it an international leader in the development of chemopreventive agents.
“The university has a tradition of excellence in many areas, but chemoprevention certainly isn’t one of them yet,” says You. “We have everything we need, in terms of the extensive cancer expertise here at the Siteman Cancer Center, the basic and clinical research expertise throughout the university, and our connections to institutions like the Missouri Botanical Garden and the Donald Danforth Plant Science Center. But the interest in chemoprevention just isn’t here yet.”
You, who has an obvious gift for confronting discouraging odds with near-manic energy and contagious cheerfulness, came to the school last year with Yian Wang, MD, PhD, associate professor of surgery. You and Wang (who are married) are both actively involved in chemoprevention research, and You has made it a priority to generate interest in chemoprevention among other Washington University faculty. He uses several scenarios to make the pitch for chemoprevention; the first comes from his research specialty, lung cancer.
“In the last few years, we have had millions of people who listened to all the information about stopping smoking and managed to stop,” explains You. “But they may then hear that they still have a significant risk of lung cancer.”
Cancer risk decreases after quitting, but only very slowly and incrementally. Thanks to the success of anti-smoking initiatives, doctors actually now see more former smokers who are first-time lung cancer patients than they do current smokers. Add this to the fact that lung cancer brings a nearly 90 percent chance of dying within three years, and many are eager to find new ways of reducing risk.
“Lung cancer is the number one cancer killer of both men and women,” he says. “If we could find a chemopreventive agent that cuts the risk of lung cancer by 50 percent, that would save nearly 100,000 lives a year.”
Another scenario You describes centers on the identification of several genes that can increase the risk of developing various types of cancer. You and Wang,
frequent research collaborators, both do research into genes
that increase risk of cancer.
Wang, who works with a rat model to study genetic factors linked to breast tumors, recently had encouraging results in an attempt to block mammary tumors that normally develop in response to a carcinogen.
“We’ve been seeing some promising preventive effects in trials of retinoids, synthetic compounds that mimic some of the properties of vitamin A,” she says.
The final scenario is a patient with a precancerous lesion. According to You, it may be possible to develop chemopreventive agents that not only help push a precancerous growth back into normalcy but also help decrease the chances that such growths will develop again.
You emphasizes that chemoprevention doesn’t guarantee a way to completely beat the odds but instead provides a method for tilting them in a patient’s favor.
“We have a goal of maximum efficacy with minimal harm, so I don’t think this approach is likely to ever prevent 100 percent of cancers,” You explains. “Chemoprevention is not like chemotherapy, where the number one concern is prolonging life at any cost. Many of the patients we hope to treat don’t have cancer yet, they just have a high risk. So they don’t want to lose hair or their appetite—they want to live normally and still prevent cancer from occurring.”
Finding new leads for potential chemopreventive agents often involves an odd mixture of investigating folk remedies and applying the latest basic research into the origins of cancers.
You describes the work of John Pezzuto, dean of the School of Pharmacy at Purdue University, as an example. The famous contrast between traditional high-fat diets in Mediterranean countries and the low rates of cancer and heart disease found in those areas led him to study the grapes that went into the region’s red wines. He found a potent anti-cancer compound called resveratrol in the skins of the grapes.
You places his laboratory halfway along the chain of development from lead to treatment. He doesn’t screen dozens of potential chemopreventives — “they’re about 90 percent wrong and 10 percent gold,” he says—but instead tests the best leads in animals and isolates the compounds providing the chemopreventive effect. His team lays the groundwork on preclinical studies that make human clinical trials possible for other, more clinically oriented research groups.
You’s lab has helped to advance two promising members of a new generation of potential lung tumor preventives. He and Stephen Lam, a pulmonologist at the University of British Columbia in Vancouver, have been working with an herbal tea mixture that a Chinese doctor, Lin Pei-Zhong, showed could reduce the rates of esophageal cancers.
“I’m normally very suspicious of herbal mixtures, but he presented solid scientific data at a conference in China in 1996 and was willing to let us work with him,” says You, who now has a paper in the works confirming the mixture’s anti-tumor effects in mice.
Lam and You also are co-principal investigators on a clinical trial to see if green tea can reduce the occurrence of lung cancer. The trial is currently underway at the University of British Columbia’s Cancer Centre.
YOU HAS MADE PROGRESS VERY RECENTLY in his efforts to interest Washington University faculty in chemo-prevention. He and Lynn A. Cornelius, MD, associate professor of medicine and head of the division of dermatology, are seeking funds to test chemopreventive agents in solid organ transplant recipients.
Transplant patients have to take immuno-suppressive drugs to prevent rejection of their new organs, but because the immune system also plays a role in fighting cancer, those drugs can combine with other factors to greatly increase the patient’s risk of skin cancers. Dermatologists estimate that transplant patients may have 64 times the normal risk for squamous cell cancer, 10 times the risk for basal cell cancer, and three times the risk for malignant melanoma.
“This has been a significant problem in the management of these patients, particularly those who are fair-skinned and have had considerable sun exposure,” says Cornelius. “This is a perfect patient population at risk for skin cancer in which to develop chemopreventive therapies.”
Physicians currently use compounds related to vitamin A to lower cancer risk, but they have serious disadvantages. Working with Daniel C. Brennan, MD, associate professor of medicine and director of the renal transplant service, Cornelius had been considering the possibilities of trying a green tea extract or omega-3 fatty acids as chemoprevention therapies. That’s when Brian Springer, research administrator at the Siteman Cancer Center, put Cornelius in touch with You.
“I am totally impressed with Dr. You’s enthusiasm and knowledge regarding chemoprevention, along with his willingness to help formulate an approach for a clinical intervention,” says Cornelius.
You hopes that Cornelius will be the first of many faculty he can assist with chemoprevention research.
“Chemopreventive agents are starting to happen for breast cancer, they’re rapidly becoming available for colon cancer, and there are even some new leads for prostate cancer,” he says. “Things are starting to happen very quickly.”