Cancer Prevention: Stopping Cancer Before It Can Start
SAN DIEGO, April 15, 2008 – 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.”
The mission of the American Association for Cancer Research is to
prevent and cure cancer. Founded in 1907, AACR is the world's
oldest and largest professional organization dedicated to advancing
cancer research. The membership includes nearly 27,000 basic,
translational, and clinical researchers; health care professionals;
and cancer survivors and advocates in the United States and more
than 70 other countries. AACR marshals the full spectrum of
expertise from the cancer community to accelerate progress in the
prevention, diagnosis and treatment of cancer through high-quality
scientific and educational programs. It funds innovative,
meritorious research grants. The AACR Annual Meeting attracts more
than 17,000 participants who share the latest discoveries and
developments in the field. Special Conferences throughout the year
present novel data across a wide variety of topics in cancer
research, treatment, and patient care. AACR publishes five major
peer-reviewed journals: Cancer Research; Clinical Cancer Research;
Molecular Cancer Therapeutics; Molecular Cancer Research; and
Cancer Epidemiology, Biomarkers & Prevention. Its most recent
publication and its sixth major journal, Cancer Prevention
Research, is the only journal worldwide dedicated exclusively to
cancer prevention, from preclinical research to clinical trials.
The AACR also publishes CR, a magazine for cancer survivors,
patient advocates, their families, physicians, and scientists. CR
provides a forum for sharing essential, evidence-based information
and perspectives on progress in cancer research, survivorship, and
advocacy.
Media Contact:
Staci Vernick Goldberg
267-646-0616
Staci.goldberg@aacr.org
In San Diego (4/12-4/16):
(619) 525-6370
Posted: April 2008
