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Targeting Inflammation in Cancer PreventionBy John LeBas
Cancer prevention specialists have long sought ways to forestall cancer in people most at risk for the disease. Because chronic immune responses appear to provoke genetic aberrations and defective cell signaling that cause many types of cancer, blocking inflammation is a logical approach to cancer prevention. Anti-inflammatory compounds have garnered much interest in the field of cancer prevention and are being widely tested, despite the somewhat rocky history of a newer subgroup of anti-inflammatory drugs known as cyclooxygenase-2 (COX-2) inhibitors. Five years ago, most testing of COX-2 inhibitors for cancer prevention was halted because of unacceptable cardiotoxicity. Since then, however, researchers have found new promise in both COX-2 inhibitors and other drugs that disrupt inflammatory pathways to cancer. Of the various reasons to continue testing COX-2 inhibitors and other non-steroidal anti-inflammatory drugs (NSAIDs) for cancer chemoprevention, the most important may be that inflammation appears to play a role in many cancer types that affect a large number of people. “We can’t always anticipate which type of cancer a patient might get. When people have risk factors placing them at an increased risk for a specific type of cancer, we can often suggest screening or preventive approaches targeted to that cancer type. But it would be even better if we could identify a drug that will prevent not just one type of cancer but many,” said Ernest Hawk, M.D., professor and vice president for cancer prevention at The University of Texas M. D. Anderson Cancer Center. “We are still looking for that Holy Grail, and targeting inflammation appears to be part of the answer.” Learning from the past The idea that inflammation leads to cancer is not altogether surprising, considering that medicine has linked an overactive or extended immune response with many ailments, including asthma, rheumatoid arthritis, and inflammatory bowel disease. Further, it has long been known that many solid tumors arise at sites of chronic irritation. The potential sources of cancer-causing inflammation include:
The administration of NSAIDs for cancer chemoprevention has been most vigorously tested in patients with familial adenomatous polyposis (FAP). In this inherited condition, mutations of the APC gene cause hundreds or thousands of colorectal adenomatous polyps, or adenomas. FAP almost always progresses to colorectal cancer by adulthood unless a prophylactic colectomy (removal of the colon) is performed. Researchers began experimenting with COX-2 inhibitors to prevent such cancers in the 1990s after a team led by Raymond N. DuBois, now provost and executive vice president at M. D. Anderson, discovered that the COX-2 enzyme was highly expressed in colorectal adenomas and colorectal cancer. FAP patients are a seemingly ideal group in whom to test cancer-preventing compounds. First, genetic testing and family history can clearly identify such patients as being very likely to develop a specific type of cancer. Second, both the COX-2 inhibitor celecoxib (Celebrex) and the NSAID sulindac (Clinoril) have been shown effective at reducing the number of polyps in FAP patients. But the risk of side effects, particularly those associated with celecoxib, has slowed the wider application of NSAIDs as chemopreventive agents. After federally sponsored trials of COX-2 inhibitors were halted in 2004 as a result of the cardiotoxicity findings in one large trial, researchers sought clues to what went wrong. In a retrospective study, they learned that a small percentage of people—those with the star-3 allele of the CYP 2C9 enzyme—do not seem to metabolize celecoxib as effectively, which leads to higher serum levels of the drug. As a result, such patients may be more likely to suffer side effects, and they probably are not good candidates for future research involving celecoxib, Dr. Hawk said. However, other factors may affect a patient’s risk of cardiac harm from the drug, and those would best be elucidated by larger prospective studies. Another recent analysis of 5-year data from earlier trials showed for the first time that celecoxib suppresses—but does not ablate—colorectal adenomas, meaning that the agent may need to be taken continuously to control the growths over the long term. Although that finding could help refine patient selection, it too needs to be confirmed with a large prospective study. New research Many of the data from celecoxib trials gathered since 2004 are preliminary or from early-phase testing, but they suggest that investigation of COX-2 inhibitors should continue. Published data from the first large randomized phase II study of celecoxib in lung cancer prevention showed not only that the drug reduced levels of a cellular proliferation biomarker in current and former smokers, but also that no adverse cardiac events occurred. The trial was among those halted in late 2004 after the cardiac risks of celecoxib were discovered; however, it reopened 6 months later after stricter guidelines were adopted to exclude those patients who were more susceptible to adverse cardiac events. “We learned that not only are COX-2 and the inflammation pathway important targets in lung cancer prevention, but that COX-2 inhibitors can be given safely to some patients at a high risk for lung cancer,” said Edward S. Kim, M.D., an assistant professor in M. D. Anderson’s Department of Thoracic/Head and Neck Medical Oncology and principal investigator for the lung cancer study.
Early analyses from other placebo-controlled phase II trials suggest that celecoxib may also reduce the incidence of cancer in some patients at high risk for bladder or skin cancer, though confirmatory data are needed. Investigation of celecoxib in patients with FAP has continued as well. M. D. Anderson was the lead institution in a recent phase II pediatric trial that aimed to determine whether celecoxib can delay or prevent the need for prophylactic colectomy in children with FAP. “Preliminary findings suggest that celecoxib, even at a high dose, is safe in children as young as 10 years old, at least when given for a short time (3 months),” said principal investigator Patrick Lynch, M.D., an associate professor in the Department of Gastroenterology, Hepatology and Nutrition. “When polyps are present, celecoxib, at least at a high dose, seems to work as well as it does in adults in shrinking or regressing adenomas.” A phase III trial is under way to see whether celecoxib can prevent the initial occurrence of adenomas in children who have APC gene mutations but who haven’t yet developed many polyps. Investigators caution that much remains to be learned about how celecoxib affects individual patients’ risk of adverse cardiac events. “Screening for cardiotoxicity is a hard one,” Dr. Lynch said. “What we do is to exclude from trials and from non-trial use of NSAIDs those subjects who have obvious preexisting cardiovascular risk factors, such as existing cardiovascular disease, hypertension, diabetes, and a strong family history of cardiovascular disease.” Based on the research from the past 5 years, COX-2 inhibitors warrant further study, Dr. Hawk believes. “If it can be definitively shown through larger trials that celecoxib can blunt the incidence of cancer in at least four organs (colon, lung, bladder, and skin), and if we can refine its administration in a safe manner, then COX-2 inhibitors may be a very powerful class of compounds for cancer prevention.” Other approaches Of course, the strategy of interrupting inflammatory pathways to cancer may not rely solely on COX-2 inhibitors, as suggested by successful studies of other agents. Dr. Hawk was the project officer for a U.S. National Cancer Institute–led clinical trial of two older drugs, sulindac and eflornithine (an inhibitor of the enzyme ornithine decarboxylase), in patients with prior colorectal adenomas. Testing in animals had demonstrated that the drugs had synergy when given in combination, suggesting that the effective dose of each agent is lower when they are given together than when they are given separately. With lower doses, the researchers expected fewer side effects (which can include cardiotoxicity from sulindac and loss of hearing and low platelet counts from eflornithine). Results of the phase II/III clinical trial, which included 375 patients, were far better than expected: the combination yielded a 90% reduction in the number of adenomas overall and a 95% reduction in premalignant adenomas. Moreover, no significant side effects were observed, though there was some indication of hearing loss and myocardial infarction in patients with certain cardiac risk factors. The study was published last year in Cancer Prevention Research. “This was arguably the first real test of combination chemoprevention,” Dr. Hawk said. “Though there is still a potential for side effects, we think the risk can be managed by giving this combination. Its effectiveness was almost comparable to that of a surgical approach.” Two trials are now being designed to test the combination in a larger group of patients, and a third trial of the combination plus celecoxib in patients with FAP is under way at M. D. Anderson and other institutions. Meanwhile, preclinical studies at M. D. Anderson are providing new knowledge about the varied ways in which inflammation can contribute to cancer—and perhaps are laying the groundwork for future preventive therapies. For example, it is strongly suspected that obesity increases a person’s risk of developing pancreatic cancer, but until recently, the exact mechanism of carcinogenesis was unknown. Then last year, a preclinical study by researchers at M. D. Anderson and The University of Texas at Austin showed that mice given a high-calorie diet developed more pancreatic tumors and pancreatic tumors of greater severity than mice given a restricted-calorie diet. Furthermore, the study showed that the restricted-calorie group had lower serum levels of inflammatory signaling proteins—a finding that made sense, according to the authors, because fat tissue is known to be a major source of such proteins. “Our findings suggest that calorie restriction could play a role in the prevention of pancreatic tumors caused by chronic inflammation,” said senior author Stephen D. Hursting, Ph.D., professor in M. D. Anderson’s Department of Carcinogenesis and chair of the Department of Nutritional Sciences at The University of Texas at Austin. In another example, M. D. Anderson researchers discovered that tumor necrosis factor alpha, an inflammatory protein, can trigger blood vessel growth (angiogenesis) in breast cancers by switching off two genes that suppress tumor formation. Since angiogenesis is crucial to tumor growth, tumor necrosis factor alpha might be a therapeutic target for some breast cancers, researchers said. In mice, injections of the immunosuppressant rapamycin interrupted the angiogenic process, presumably by blocking the molecular signaling that switched off the tumor-suppressing genes. The group, led by Mien-Chie Hung, Ph.D., professor and chair of the Department of Molecular and Cellular Oncology, is now trying to determine whether the tumor pathway elucidated in the study helps explain why obese people may be at a higher risk of developing pancreatic and other cancers, since obese mammals have been shown to have high levels of tumor necrosis factor alpha in their fat cells. Given the complexity of inflammation’s role in cancer development, it could be that not one but many Holy Grails will someday be used to prevent inflammation from causing tumors. “I don’t anticipate that any of these agents are chemotherapeutic—they aren’t going to wipe out a cancer,” Dr. Hawk said. “But for the prevention of certain cancers, they may ultimately prove to be very effective.”For more information, visit M. D. Anderson’s Web site at www.mdanderson.org. Other articles in OncoLog, May 2009 issue:
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