Chemoprevention backgrounder: Working for a future of cancer chemoprevention
Nowadays, a vial of blood taken by a family physician can sometimes forecast a person’s risk of heart disease, and cholesterol-lowering drugs as well as a daily baby aspirin may be recommended to curb the threat. But in the future, a simple finger prick also may predict which cancers are destined to develop in an individual, years, even decades, down the road.
And based on a person’s unique genetics - the milieu of factors that repair DNA damage, or push cells to grow - the patient of tomorrow also may be given a recipe of drugs that will prevent or delay those cancers from ever developing. Their cocktail of cancer preventives might include refined forms of aspirin to prevent colon and breast cancer, trace minerals to protect against prostate cancer, or proven versions of ancient remedies, such as turmeric spice for breast cancer and good ole’ cups of green tea daily, to repress oral cancer. At the moment, a complete "chemoprevention" strategy - the use of a natural or synthetic substance to reduce the risk of developing cancer - is a goal to be reached in the future. By all accounts, routine use of such agents won’t be here for a long time because much more needs to be understood about the changes that push a cell to become cancerous before that process can be stalled or reversed.
Still, more and more of the research effort at The University of Texas M. D. Anderson Cancer Center is devoted to finding such preemptive strikes - ways to block cancer from ever starting or from becoming clinically apparent. M. D. Anderson was among the first to look for agents that may help prevent cancer - some three decades ago - and now is seen as a national leader in the field of chemoprevention. In fact, four of five classes of chemopreventive agents the National Cancer Institute has said are promising and so are "considered priority substances for study" are being investigated here, and some of the efforts involve national trials being led by M. D. Anderson researchers. Those compounds are retinoids, nonsteroidal anti-inflammatory drugs (NSAIDs), calcium compounds and selective estrogen receptor modulators (SERMs).
The research represents a completely new way of thinking about cancer, says Waun Ki Hong, M.D., head of the Division of Cancer Medicine at M. D. Anderson. "Cancer doesn’t begin with the appearance of a tumor, just as cardiac disease doesn’t start with a heart attack," he says. "And just as we can control the risk of a heart attack with medication, we want to control the process of cancer development with drugs and supplements," says Hong, who is credited as a national pioneer in the chemoprevention movement, an effort he started at the Boston VA Medical Center before he moved to M. D. Anderson in 1984. In 2003, the American Association for Cancer Research (AACR) and the Cancer Research and Prevention Foundation (CRPF) recognized Hong with its second annual AACR-CRPF Award for Excellence in Cancer Prevention Research. The previous year’s inaugural award went to Michael B. Sporn, M.D., of Dartmouth Medical School, for his work on the basic science of chemoprevention. "As complicated as cancer is, oncology is decades behind cardiology in this respect, but we will get there. It is just going to require a lot of patience and hard work." Adds Bernard Levin, M.D., vice president for Cancer Prevention and Population Sciences at M. D. Anderson, "Our work will never be done until we can say that we have reduced the risk of developing cancer very substantially - perhaps down to zero."
The retinoid story - first bid to reverse damage When Hong began his work on chemoprevention three decades ago, researchers knew very little about the genetic changes that push a normal cell to divide and survive - the cross-circuitry that produces cancer. And they were still honing use of the tools that helped them cut out tumors (surgery), zap cancer from outside (radiation), or blast it from the inside (chemotherapy). But Hong worked in the field of head and neck cancers, which, along with lung cancers, are among the most common and most difficult to treat. Many of these cancers are associated with smoking, so Hong reasoned that if he could find genetic changes in cells lining the airways that are exposed to carcinogens, then targeting these "precancer" cells for treatment could delay the onset of cancer in some people. Hong did find an "initiation phase" in which genetic changes produce premalignant lesions, which then can morph into full-blown cancer cells. He then collaborated with Reuben Lotan, Ph.D., now a professor in the Department of Thoracic/Head and Neck Medical Oncology, who had been studying the role of vitamin A (retinol) and its chemical cousins, known as retinoids, in cancer cell growth and death. Lotan suspected, and later proved, that tobacco smoke hampered efficient functioning of retinoids, and after a series of experiments, Lotan and Hong began to study whether retinoids could reverse precancerous changes in the lungs of former smokers.
Thus, the first such chemoprevention trial of its kind was launched. In the early 1990s, they demonstrated that high dose retinoids could, indeed, stop precancerous growths in the mouth and oral cavity from turning into cancer, allowing them to return to a normal state. The pioneering work provided the first proof that cancer could be reversed. That effort continued. A different formulation of retinoid, known as 13-cis retinoic acid, has been found to prevent the development of second primary tumors in patients who have successfully completed treatment for head and neck cancers. Scott Lippman, M.D., professor and chair of M. D. Anderson’s Department of Clinical Cancer Prevention, led the phase III trial, testing 13-cis retinoic acid in 1,265 patients with early stage lung cancer. Yet another chemical cousin has shown itself to be a chemopreventive. Lotan and associate professor Jonathan Kurie, M.D., discovered in a trial of 226 patients that 9-cis retinoic acid restored health to lung cancer cells that were already precancerous.
Despite the fact that the researchers suspect retinoids may ultimately prove to be too toxic for everyday use, these studies have lead to important insights. And they earned M. D. Anderson four large federal grants of more than $30 million over the past 13 years to expand and build upon its comprehensive lung cancer chemoprevention study. The funds pay for chemoprevention trials as well as parallel genetic, molecular and pharmacologic studies in the lab, says Hong, all aimed at putting a damper on the world’s most dangerous cancer. "Super aspirins" tested in leading cancer killers One third of all cancer cases are associated with smoking tobacco, so, of course, the best way to prevent those cancers is to never pick up a cigarette, or to throw them away.
But while the 45 million people in the United States who have quit smoking have reduced their risk of developing lung cancer, the genetic damage caused by smoking does not entirely disappear, M. D. Anderson researchers say. Half of all newly-diagnosed lung cancers occur in former smokers, and so investigators are trying other ways, besides retinoids, to prevent the genetic damage from turning into cancer. One of the most promising approaches to lung cancer chemoprevention is the use of a so-called "super aspirin," says Kurie, in the Department of Thoracic/Head and Neck Medical Oncology. He is conducting a clinical trial testing whether celecoxib, a non-steroidal anti-inflammatory drug (NSAID) known by the trade name Celebrex, can repair precancerous lung damage in current and former smokers. Celecoxib works by blocking of cycloxygenase-2, or "COX-2," an enzyme that is over-produced when cells become inflamed. Studies have shown, however, that many tumors, including those for small-cell lung cancer, also contain a lot of COX-2, possibly because of the body’s natural immune reaction to the cancer. Lotan found this year that, like some retinoids, NSAIDs may be effective in controlling cancer because they push cancerous cells to self-destruct.
In the ongoing placebo-controlled trial, which has accrued 85 patients so far, Kurie takes a biopsy of lung cells before, after and during the six-month study to see if twice-daily 400 milligrams doses of celecoxib can reverse damage due to smoking. "It’s a biomarker study in which we will be able to see evidence of activity quickly," he says. "If positive, we will move on to a national study." Not only is the power of COX-2 inhibitors being tested at M. D. Anderson in the number one cancer killer, lung cancer, but in the second deadliest national cancer - colorectal cancer.
And so far, it already has been proven to have an effect in people who inherit a form of colon cancer known as familial adenomatous polyposis (FAP), in which hundreds of precancerous polyps form in the colon and rectum. In 1999, the Food and Drug Administration (FDA) approved the use of celecoxib for FAP patients, based on work conducted at M. D. Anderson and St. Marks Hospital in London. In the study, led by Patrick Lynch, M.D., celecoxib reduced the number of polyps by 30 percent. "It was an important event in the field of chemoprevention," says Levin. Colorectal cancer prevention trials do not focus on cancer occurrence, because of time constraints, but rather look at the incidence of adenomatous (glandular) polyps, which are known to increase colon cancer risk.
Based on that study, Lynch, an associate professor in the Department of Gastrointestinal Medicine and Nutrition, is heading another international trial in FAP looking at use of celecoxib combined with eflornithine (DFMO), a drug used to treat African sleeping sickness, but which is suspected of having anti-cancer properties. Yet another trial, led by Lynch, will be evaluating the efficacy of celecoxib in children who are carriers of the mutated FAP gene, and who have little or no evidence yet of polyps. This international study will follow the recently completed pediatric phase I trial conducted by Lynch and colleagues at the Cleveland Clinic. Levin is researching the issue as co-principal investigator of a multi-center international trial of celecoxib, evaluating its role in preventing recurrence of precancerous polyps.
Researchers say that any drug used for a long time has to be proven to be safe, and that is equally true for the popular COX-2 inhibitors, which are most often used to treat arthritis and pain. For example, a different COX-2 inhibitor drug known as Vioxx was withdrawn from the market in September, 2004, because it doubled cardiovascular problems in a clinical trial testing if it could prevent colon polyp recurrence. Clinical trials such as Levin’s that is testing celecoxib, also as a chemopreventive against recurrence of large polyps, have not been halted although data is being intensely scrutinized by cardiovascular experts for similar problems to assure long-term patient safety. Aspirin, which also has the properties of a COX-2 inhibitor, has itself shown that it may help prevent colon cancer. A study published last year in The New England Journal of Medicine showed that a low-dose baby aspirin proved effective as a modest colon cancer chemopreventive, reducing the number of precancerous polyps by 19 percent.
Results from the prospective, randomized clinical trial of more than 1,000 participants, offered "the strongest indication to date that aspirin can have a significant effect on recurrence of colon adenomas," says one of the study’s lead researchers, Robert Bresalier, M.D., professor and chair of the Department of Gastrointestinal Medicine and Nutrition at M. D. Anderson. Surprisingly, the study found that the effect of a baby aspirin was greater than that of a full strength tablet, which only reduced polyps by four percent. Research is under way to understand why this is so. Bresalier also is studying the effect of taking a combination of vitamin D and calcium on the development of polyps in people who are an average risk for developing colon cancer. Previous work has suggested that both supplements could offer some protection, so "it makes sense to look at them together," says Bresalier. The 2,400-participant trial is being conducted at nine institutions, including M. D. Anderson.
And still other strategies to prevent colon cancer also are being tested here, including a clinical trial that pits aspirin against the NSAID Sulindac. Despite promising results testing COX-2 inhibitors, none of M. D. Anderson’s researchers suggest that healthy people take these drugs to ward off cancer. "We need to be sure that the long-term benefits of these and other chemopreventives outweigh any major side effects before prescribing these medications for continuous usage over many years," says Levin.
Lotan suspects that for long-term cancer control, people may benefit from combining an NSAID with a safe synthetic retinoid known as fenretinide, which has been shown in an Italian clinical trial to help premenopausal women control their risk of breast cancer. Researchers at M. D. Anderson plan to initiate such a trial. "People are probably impatient with us, hoping that we can say they should take a baby aspirin for the rest of their lives to prevent cancer," says Hong. "But I don’t think aspirin by itself is strong enough, or good enough, to modulate carcinogenesis." Agents to ward off top gender-based cancers M. D. Anderson physicians and researchers also have been taking on the two big gender-specific cancers - breast and prostate - in both large and small chemoprevention studies. In breast cancer, the researchers are intent upon improving what is already the biggest chemoprevention success story to date - the use of tamoxifen, a selective estrogen receptor modulator (SERM), to ward off recurrence of breast cancer.
M. D. Anderson, as a single institution, was the largest recruiter of patients nationally in the trial that proved the value of tamoxifen. Under the guidance of Therese Bevers, M.D., an associate professor of the Department of Clinical Cancer Prevention and director of the Cancer Prevention Center and the Prevention Outreach Programs,M. D. Anderson also is one of the top recruiters in the trial that is now seeking to find a better alternative to tamoxifen. Tamoxifen blocks the effects of the estrogen in the body, and because 80 percent of breast cancers are dependent on estrogen hormones, the drug has a powerful anti-cancer effect - it decreases the risk of invasive cancer by half in women at risk, says Bevers. But tamoxifen is associated with some serious side effects, so researchers are testing the newer SERM, raloxifene, in one of the largest breast cancer prevention studies ever. The trial, known as STAR (The Study of Tamoxifen and Raloxifene), has recruited more than 19,000 volunteers at more than 400 centers, including 217 at M. D. Anderson, and an additional 170 at M. D. Anderson satellite sites.
Raloxifene, used to prevent osteoporosis, may have fewer side effects than tamoxifen, Bevers says. But while the results of STAR likely will be known in the next year or two, approaches are being investigated at M. D. Anderson that will help speed up investigation of even newer classes of estrogen blockers and other chemopreventive agents such as COX-2 inhibitors, she says. For example, Banu Arun, M.D., is identifying biomarkers in breast cancer cells that will quickly tell researchers whether or not potential chemopreventive drugs are having any effect. "This is so important because long-term chemoprevention trials are expensive and take a long time to conduct. It would be best if promising agents can be screened first," says Arun, an associate professor in the Department of Breast Medical Oncology. "Evidence taken directly from these studies will help move larger chemoprevention studies forward."
Arun is looking for such markers in an M. D. Anderson clinical trial testing use of celecoxib in preventing breast cancer - believed to be the only trial of its kind in the United States. She also is researching how the newest classes of estrogen blockers change the biology of breast cells. To do that, Arun uses a minimally invasive technique known as ductal lavage to collect and examine cells from breast milk ducts. She says that, so far, "COX-2 overexpression is strongly implicated in progression of breast precancer to malignancy." Retinoic acids also are being tested as a breast cancer chemopreventive. Gordon Mills, M.D., Ph.D., a professor and chair of the Department of Molecular Therapeutics, is examining the effects of retinoic acid and birth control pills on breast and ovarian tissue in patients who have a strong family history of the disease.
Hints that prostate cancer also may respond to a strategy of chemoprevention has lead to the largest cancer prevention study ever undertaken - a study of selenium and vitamin E supplements in 32,400 men across the United States, Canada and Puerto Rico. Known as SELECT (the Selenium and Vitamin E Cancer Prevention Trial), the trial is based on observations from two previous studies that failed, but which offered a new direction, says Lippman, the national medical oncology leader of the trial, which is expected to take more than a decade. One earlier study had tested whether selenium, a trace element, could help prevent non-melanoma skin cancer. In the end, skin cancer rates were not reduced, but the expected incidence of prostate cancer fell by two-thirds. The other study explores use of vitamin E to prevent lung cancer, and results showed no effect of vitamin E on lung cancer rates, but prostate cancer incidence fell. Data from cell and animal studies also suggests that selenium "may slow the progression of subclinical prostate cancer, which is equivalent to prevention," says Lippman.
Not only is Lippman a national coordinator of SELECT, but he also serves as M. D. Anderson’s principal investigator on a newly created consortium of six research centers that are working together on cancer prevention. The National Cancer Institute’s Division of Cancer Prevention recently devoted $42 million to the group, directing them to work as hard and fast as they can on the development of cancer preventive compounds. Projects funded by the consortium cover the spectrum of cancers and are designed to quickly test the cancer preventive potential of new agents. But several of the first studies launched at M. D. Anderson are looking at very old remedies.
Arun, for example, is intrigued by the Far Eastern spice turmeric (also known as curcumin), which has demonstrated anti-cancer properties in laboratory and animal studies of lung, colon and breast cancer conducted by Bharat Aggarwal, M.D., a professor in the department of Bioimmunotherapy Research. "This Far Eastern spice, one of the main ingredients of curry, has been used medicinally and as a food for centuries, and has no side effects, which makes it an ideal chemoprevention agent," says Arun. "We are finding curcumin can suppress markers of cell proliferation." And Vassiliki Papadimitrakopoulou, M.D., an associate professor in the Department of Thoracic/Head & Neck Medical Oncology, is testing whether the active substance contained in green tea, epigallocatechin gallate, can act like an anti-cancer drug, stopping precancerous lesions in the mouth and throat from morphing into tumors.
Green tea has long been suspected of having beneficial health effects, based on decades of research conducted in China, Southeast Asia and Japan. "Epidemiological studies conducted in the 1980s suggested that people in those countries who drink a certain number of cups of green tea, or more, each day, appear to be protected against a variety of cancers, including stomach, prostate, colorectal, and head and neck cancers," says Papadimitrakopoulou. New laboratory research has found that epigallocatechin gallate, a tannin with potent antioxidant activity, suppresses signals that instruct a cell to grow. In Papadimitrakopoulou’s ongoing "blinded" study, volunteers with precancerous conditions of the oral cavity are split into four groups, three of which are given different doses of a pill that contain the green tea extract. The other group is given an inert "placebo" tablet.
At the start and end of the three-month trial, which has recruited 21 patients so far, volunteers are given a biopsy of the worrisome lesion. Results so far "have been encouraging," says Papadimitrakopoulou. "From a natural pool of agents that we are studying, this is one of the most promising." The (bumpy) road ahead What most excites Lippman and other researchers at M. D. Anderson is the notion that cancer and other common diseases of aging may be linked by common pathways that could be strategically disrupted by simply taking pills every day.
And the current number one pathway candidate, in many researchers’ eyes, is inflammation, the immune system’s reaction to cell and tissue injury. Cancer often originates at the site of chronic inflammation, and the interplay between the two is being increasingly studied. Lippman ticks off on his fingers the role that inflammation plays in "heart disease, Alzheimer’s disease, the chronic diseases associated with aging, and even obesity," and says that NSAIDs and statins, which also reduce inflammation, are now being tested in cancer, as well as in Alzheimer’s disease; aspirin and statins, he further notes, have long been used to prevent heart attacks. Whether it is NSAIDS, statins or any agent, "the science behind inflammation is moving so rapidly that we may now be able to think about designing trials to test agents that will prevent, or delay, several diseases all at once," says Lippman. Still, none of M. D. Anderson’s chemoprevention experts - including Lippman, Lotan, Levin and Hong - suggest that people take a little celecoxib here, a dose of aspirin there, or mix tablespoons of turmeric into their cups of green tea as a way to "self medicate" against cancer.
They all stress that it will take time to prove that any substance can substantially reduce the risk of a disease in the average person without producing side effects. These studies will require giving young and healthy volunteers a drug for many years and then waiting until they have aged to see whether volunteers who used the agent developed fewer diseases compared to those who didn’t. "Like testing whether fluoride in water can prevent cavities, we will not have an answer for 20 to 25 years in the minimum," says Lotan. "You have to make sure that these agents have no side effects if taken for decades, and that is a risk not many drug companies or institutions want to take."
Most chemoprevention studies now test people who are at higher risk of developing cancer, such as former smokers, as a way to predict whether they will help those who are not at risk; few studies are like SELECT in which the only risk factor shared by participants is increased age. At the same time, researchers at M. D. Anderson are actively looking for molecular and genetic risk factors that identify people at highest cancer risk and those most likely to benefit from chemoprevention. "We must do no harm," says Hong. "A cancer chemoprevention agent, used in young people who are not at risk for cancer, must be absolutely safe and non-toxic." Levin and others emphasize that chemoprevention must not be substituted for other important lifestyle habits such as avoiding tobacco and exercising. "Still, while we should be modest in claiming our work in the next decade will lead to new chemoprevention advances, we have promising leads from the laboratory that will enable us to conduct good trials in the future," says Levin. "The best is yet to come."
Nancy Jensen | EurekAlert!