Cancer prevention

Tapping into a growing body of knowledge about the origins and progression of cancer, researchers are now developing and testing new preventive therapies to stop it in its tracks.

At the 2008 Annual Meeting of the American Association for Cancer Research, April 12-16, researchers present data on the preventive effects of celecoxib and atorvastatin and vitamin D in colorectal, prostate and breast cancer, respectively, and the relationship between diet, metabolism and the development of pancreatic cancer.

The Adenoma Prevention with Celecoxib (APC) trial: Five-year efficacy and safety results: Abstract LB-141

Colon adenoma prevention with celecoxib, a non-steroidal anti-inflammatory drug (NSAID), is effective and can be safe for patients without underlying cardiovascular risk factors, according to five-year data of a randomized phase III trial.

“There has been a significant amount of negative press about Cox-2 inhibitors including celecoxib, and clearly these drugs are risky for some patients. However, our study also shows that for patients without major cardiovascular risk factors, celecoxib at low doses protects against high-risk lesions that can lead to colon cancer,” said Monica Bertagnolli, M.D., associate professor of surgery at the Brigham and Women's Hospital.

Bertagnolli was the lead researcher on the Adenoma Prevention with Celecoxib (APC) trial, which enrolled 2,035 patients and randomly assigned them to 200 mg twice-daily (400 mg) of celecoxib, 400 mg twice-daily (800 mg) of celecoxib or a placebo group.

At three years, patients taking celecoxib at 400 mg had a 29 percent reduction in adenomas, a precursor to colon cancer, while those taking 800 mg had a 38 percent reduction. Advanced adenomas, which are lesions with a high-risk for cancer development, were reduced by 55 percent with 400 mg and 63 percent with 800 mg.

After three years, patients stopped taking celecoxib and were followed for another two years to assess safety and effectiveness. Even after two years off medication, the five-year rate of advanced adenoma was reduced by 41 percent among patients taking the lower dose and 26 percent among patients taking the higher dose.

Cardiovascular events were more common in patients taking celecoxib, with a rate of 3.8 percent among those patients taking placebo to 6 percent among the low dose group and 7.5 percent among the high dose group. However, when researchers looked at factors that might predict cardiovascular complications, they found a much different story.

For patients with no cardiovascular risk factors before using celecoxib, the rate of cardiovascular adverse events was 0.9 percent in the placebo group, 3.9 percent in the 400 mg group and 1.9 percent in the high dose group. Cardiovascular risk factors included smoking, high cholesterol, high blood pressure, diabetes, presence of atherosclerosis and age over 65.

If a patient had one risk factor, the risk was 2.2 percent in the placebo group, 3.7 percent in the 400 mg dose group and 4.9 percent in the high dose group.

The greater cardiovascular risk was observed among patients who had at least two cardiovascular risk factors at the time they entered the study, where the placebo group had a 5.9 percent risk, the 400 mg group had an 8.2 percent risk and the 800 mg group had an 11.2 percent risk.

“This new data allows us to carefully select patients who can benefit from this drug,” Bertagnolli said. “Although it should be used with caution, those patients with a high risk for colon cancer and a low risk for cardiovascular disease are going to receive significant benefit.”

Inhibition of androgen-independent growth of LNCaP xenograft tumors in immunodeficient mice by a combination of atorvastatin (Lipitor) and celecoxib (Celebrex): Abstract 2100

Suggesting a new role for the prevention of advanced prostate cancer by two commonly prescribed drugs, researchers found that a combination of atorvastatin and celecoxib potently inhibited the androgen-independent growth of prostate tumors in a laboratory model.

“This represents a viable prevention strategy to stop the progression of prostate cancer from androgen-dependent to androgen-independent, which is much more aggressive and has limited therapeutic options,” said Xi Zheng, Ph.D., M.D., assistant research professor at Rutgers University in New Jersey.

Previous epidemiology research has shown that statins like atorvastatin and non-steroidal anti-inflammatory drugs (NSAIDs) like celecoxib may reduce the risk of prostate cancer. Zheng and colleagues assessed the effects of atorvastatin and celecoxib alone or in combination on androgen-independent growth of human prostate cancer cells cultured in vitro or grown as tumors in mice.

In the animal study, mice with an androgen-dependent tumor were deprived of androgen and randomly assigned to four groups: those receiving either 10 micrograms/gram body weight per day of atorvastatin or the same dose of celecoxib; those receiving a combination of each drug at 5 micrograms/gram body weight per day; or a control group receiving no drugs.

All mice had temporary tumor regression in the absence of androgen, but then the untreated mice experienced substantial tumor regrowth as the tumor become androgen-independent. Mice treated with a single drug had some reduction of androgen-independent tumor growth, while administration of atorvastatin and celecoxib in combination resulted in a more potent inhibition of androgen-independent growth than either drug alone. “The agents appear to work by inhibiting a signal transduction pathway that is important for the growth of these cancer cells,” Zheng said.

Although a high dose of celecoxib has been linked to a small increase in cardiovascular risk in prior human studies, Zheng said the dose used in this study was low and the benefits should outweigh the risks.

Dietary energy balance impacts spontaneous pancreatic lesions in the K5.COX-2 transgenic model of pancreatic cancer: Abstract 4188

Shedding light on the links between obesity and cancer, researchers at the University of Texas M. D. Anderson Cancer Center report that modulating energy balance by restricting calories can prevent pancreatic cancer in laboratory models.

“We are very excited that our research may lead to insights to prevent or control this deadly disease in the near future,” said lead researcher Laura M. Lashinger, Ph.D., a post-doctoral fellow at M. D. Anderson.

Pancreatic cancer is the fourth leading cause of cancer death in both men and women in the United States. Obesity, the overall rate of which has risen sharply over the past 40 years, has emerged in epidemiological studies as a key risk factor for pancreatic cancer.

Other studies have shown that calorie restriction, a dietary strategy for inducing negative energy balance and preventing or reversing obesity, has significant anticancer effects in several species, against a variety of tumor types. However, the exact mechanisms underlying the obesity-pancreatic cancer association are not clearly understood.

“It is likely that inflammation may be playing a role,” Lashinger said. “Fat tissue is more than simply weight; it produces an inflammatory property that leads to greater risk of cancer and other diseases.”

In the current study, Lashinger and colleagues hypothesized that spontaneous tumor development in the K5.COX-2 transgenic mouse model of pancreatitis-driven pancreatic cancer would be reduced in lean mice, when compared with overweight or diet-induced obese mice.

They placed 36 mice on one of three diets for 14 weeks: a lean diet with a 30 percent calorie restriction (n = 12), an overweight diet (n = 12), or a high calorie, high fat diet–induced obese regimen (n = 12).

The mice developed spontaneous pancreatic lesions as early as four weeks, with 100 percent approaching death within six to eight months, the researchers report. The calorie-restricted animals were significantly protected from spontaneous formation of pancreatic lesions: 7.5 percent of them developed lesions in stark contrast to 45 percent of the overweight group and 57.5 percent of the diet-induced obese group, the researchers report. Furthermore, calorie-restricted mice had smaller lesions than those in the overweight and diet-induced obese groups.

Gemini vitamin D analogs inhibit estrogen receptor positive and estrogen receptor negative mammary tumorigenesis without hypercalcemic toxicity: Abstract 2097

Researchers at Rutgers University have found that, in animal studies, a synthetic form of active vitamin D has a substantive preventive effect on the development of both estrogen receptor (ER)-positive and ER-negative breast cancers. Unlike many of the other synthetic vitamin D agents that have been tested in humans, this compound, known as Gemini 0097, shows no toxicity, they report.

The research team found that daily injections of Gemini 0097 cut growth of ER-positive cancer by 60 percent in rat studies, and reduced ER-negative breast cancer by half in mice.

“These are very promising findings, especially because no toxicity is observed,” said researcher Hong Jin Lee, a graduate student at Rutgers. Lee works in the laboratory of lead investigator Nanjoo Suh, Ph.D., an assistant professor at the Susan Lehman Cullman Laboratory for Cancer Research at Rutgers, the State University of New Jersey. Suh said that Gemini 0097 likely did not cause the most common vitamin D toxicity, an overload of calcium in blood known as hypercalcemia, because the compound has an extra side chain of chemicals.

“It is quite different from the natural shape of active vitamin D,” she said. “Because the binding affinity of Gemini 0097 with vitamin D receptor is low that may contribute to the lower toxicity, but the efficacy stays the same or even better.”

Epidemiologic studies have shown that use of vitamin D is beneficial in preventing colon cancer, but studies in prostate and breast cancer have yielded mixed conclusions, Suh says.

Vitamin D is a pro-hormone that is produced in the skin after exposure to sunlight. Vitamin D dietary supplements are converted into an active, useful form by metabolism in the liver and kidneys. Although the active form of vitamin D has been tested as a cancer treatment, the higher doses needed for prevention or treatment have typically produced intolerable side effects in clinical trials, Suh says.

In this study, the researchers tested 60 novel Gemini vitamin compounds, with Gemini 0097 performing the best, Lee says.

In one set of studies, the researchers exposed rats to a mammary carcinogen, then injected groups of 15 animals with different doses of Gemini 0097. They found that the lowest dose had little effect but higher doses slowed the growth of resultant ER-positive tumors by 60 percent, compared with a group of control rats. Some treated rats developed small mammary tumors and some developed none at all, says Lee. “The data are very convincing,” he said.

In a second, similar experiment in a mouse model of ER-negative breast cancer, mice treated with Gemini vitamin D had 50 percent fewer tumors than did control mice.

The researchers analyzed tumor samples from both the rats and the mice and discovered that Gemini 0097 prevents tumorigenesis by increasing expression of the p21 protein, which arrests the cell cycle, and by inducing insulin-like growth factor binding protein–3 (IGFBP-3), which slows down cell proliferation.

“These data are from animal studies, and we need more data before these compounds can be tested in humans,” said Suh. “Still, we are hopeful that we have found a way of providing vitamin D without toxicity that has a significant effect on cancer prevention.”