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HOUSTON, Dec. 16 /PRNewswire/ -- Its a question that has emerged in the
past 20 years, given advances in screening and early diagnosis, rapid
developments in genetics and molecular biology, and progress in the treatment
of early disease and in next-generation targeted therapies.
And finding answers is one of the top goals of The University of Texas M.
D. Anderson Cancer Center, which has one of the largest cancer prevention
research programs in the world.
M. D. Anderson was among the first to begin dedicated prevention research
efforts in the late 1970s. A decade ago, nine faculty were working on 23
projects -- a pursuit that was regarded as trend-setting at the time. The
cancer centers focus on prevention has grown so much in recent years that the
48 faculty, involved in 140-plus research projects and clinical programs
valued at more than $20 million in 2005 alone, just moved into the new Cancer
Prevention Building.
In addition to housing faculty offices, the buildings Cancer Prevention
Center and new Behavioral Research and Treatment Center provide advanced early
detection and risk-reduction services and state-of-the-art biobehavioral and
psychosocial research venues.
These two centers involve only a sliver of the basic and applied research
under way. In short, the researchers, physicians, nurses, employees and
volunteers that staff this building aim to bring about a future that may some
day be free of cancer.
They also are the first to say that attaining this goal will not be easy;
that prevention will require developing a wide variety of strategies and
associated tactics to curtail the variety of different diseases, all called
cancer, that have now emerged as the number one killer of Americans under age
85.
"Prevention is very broad," says Bernard Levin, M.D., vice president and
head of the Division of Cancer Prevention and Population Sciences. "It is not
just prevention of cancer development, but includes advances in diagnosis and
treatment that reduce suffering and mortality from the disease."
In short, "prevention," as oncologists use the term spans the gamut from
stopping cancer from ever developing to improving cure rates through earlier
detection, thereby preventing recurrence and death. Prevention also
encompasses preventing suffering from cancer by controlling pain and meeting
psychosocial needs.
Because we see prevention as so inclusive, the task we have set for
ourselves is very difficult and wont likely be accomplished for decades,"
Levin says. "But if we can lessen the odds that even one person will develop
cancer, or suffer or die from it, we have moved one step closer to our goal.
It is that march of progress over time that will make a difference in the
future."
Developing a model of cancer prevention
Debate exists on how many cancer deaths are preventable in principle --
estimates range from 50 percent to 80 percent -- but most researchers agree
that tobacco use (mostly smoking) accounts for the majority. Today, cigarette
smoking claims about 438,000 premature deaths in the U.S. annually. It is
responsible for up to one-third of all cancer deaths and accounts for 20
percent of annual U.S. mortality due to all causes, according to the federal
Centers for Disease Control and Prevention.
And while lung cancer is tobaccos primary killer, smoking also is
responsible for many other types of tumors. Since the same carcinogens that
cause lung cancer also affect the lining of the entire respiratory tract and
are absorbed by the blood and then excreted as waste, smoking is a major cause
in cancers of the oral cavity, pharynx, larynx, esophagus, pancreas, stomach,
kidney and bladder, among others. The American Cancer Society states that
smoking damages almost every organ in the body.
The cumulative consequence of other lifestyle factors on cancer risk such
as obesity, physical activity, diet/nutrition and alcohol use, as well as
infectious agents and occupational exposures, is not fully known, although
some experts say it may approach that of tobacco use.
Given the certainty that the number one cause of cancer illness and death
is also the most preventable, scientists to date have aimed much of cancer
prevention science on smoking. "Because tobacco is responsible for an
impressive one-third of cancers, prevention efforts naturally begin with it,"
Levin says.
But he and colleagues in the Division of Cancer Prevention and Population
Sciences have moved beyond solely delivering advice to stop smoking.
They are developing a comprehensive program that not only devises
innovative behavioral and pharmacological approaches to smoking prevention and
cessation, but burrows down to the molecular level on every aspect related to
prevention.
For example, researchers at M. D. Anderson are looking at brain
physiology; variations in genes that "favor" smoking and other addictive
behaviors; genes that either protect people from developing cancer or put them
at greater risk; and genes that either aid or thwart cancer treatment.
The goals of such research, Levin says, are to be able to:
* Predict those people who might be most susceptible to smoking and to
help them resist smoking initiation;
* Provide more effective cessation assistance to those who are already
smoking;
* Help prevent development of cancer by use of chemoprevention
strategies;
* Understand the biological processes that make some smokers more
susceptible to different cancers; and
* Offer tailored treatments based on tumor and genetic profiles in each
patient to help prevent further disease.
If such a global program can reduce tobacco-related cancers, then the same
approach might work for cancers influenced by poor nutrition, lack of exercise
and excess body weight, and other such factors, Levin says. Add in prevention
screening and it makes sense why Levin says "the future of cancer prevention
is an integrated approach."
Biobehavior in the cancer formula
Two facts about smokers rivet cancer researchers: the notion that not
everyone who tries cigarettes becomes addicted, and the knowledge that only a
fraction of long-term smokers (about 15 percent) will develop lung cancer,
although tobacco also is responsible for one-third of all cardiovascular
deaths under age 85.
Innate differences exist between non-smokers and smokers in terms of
"biobehavior," such as a need for nicotine, the way different societal
cultures view smoking and how they respond to clinical treatment. Within the
divisions three groups -- the Department of Health Disparities Research, the
Department of Behavioral Science and the Department of Epidemiology -- are
investigating aspects of these topics, often in collaboration.
Differences also are likely between smokers in their physiological
responses -- how their bodies vary in susceptibility to the cancer-causing
compounds in cigarettes -- which implies that agents might be designed that
help prevent cancer from developing or treat it more effectively if it does.
To explore these topics, other teams of researchers in the Department of
Epidemiology and the Department of Clinical Cancer Prevention are working
together.
The Department of Behavioral Science is unique in the United States, says
its chair clinical psychologist Ellen R. Gritz, Ph.D. "It is a fully
established department, with resources and faculty, as opposed to a program,
which many cancer centers have."
This department "focuses on the human side of cancer -- the continuum from
risk behaviors that cause or contribute to cancer to the psychosocial factors
that affect treatment outcome, adjustment and survival," Gritz says.
"Our goal in smoking-related research is to detect those who are
susceptible to nicotine, identify the best ways to prevent these persons from
beginning to smoke and, if they do, determine how best to break the nicotine
addiction that can result," Gritz says.
The Departments longstanding efforts in this field have helped the
institution enroll thousands of smokers in numerous smoking cessation studies.
Among their notable achievements to date are:
* Development of a "scheduled smoking" approach to quitting, in which a
smoker is prompted by a hand-held computer to smoke on a schedule with
increasing intervals between prompts;
* Creation of a teen-savvy computerized classroom program (ASPIRE - A
Smoking Prevention Interactive Experience) that has resulted in lower
rates of smoking in high school; and
* Increased smoking cessation among junior high school students using
computerized, personal health status feedback techniques.
Work is ongoing on several dozen other tobacco-related studies. Among
them are:
* A randomized, controlled trial in 16 Texas rural and urban communities,
which aims to design and test an intervention protocol for training
physicians and pharmacists to effectively counsel their patients for
smoking cessation;
* A project which tests a motivational intervention protocol for smoking
cessation among students at the University of Houston. Individual
smoking cessation treatment sessions are combined with internet "cyber-
support" available 24/7;
* Research to derive factors that predict onset of smoking in white,
Hispanic and African-American youth;
* Multiple studies on the role of depression in smoking behavior and
smoking cessation. For example, one involves tracking depression in
pregnant smokers, based on earlier findings that depression makes it
harder for smokers to quit;
* Research on special populations of smokers, including low income,
multi-ethnic HIV-positive persons;
* Research that examines the cognitive processes underlying addiction,
such as the physical response in the brain to drugs used to treat
nicotine dependence; and
* An investigation of why some cancer patients continue to smoke, and how
they can be helped to stop during treatment and throughout survival.
The risk-related and behavioral research methods used to study smoking
have been adapted by researchers in the department to look at other
preventable cancers, such as skin cancer, melanoma and colon cancer, Gritz
says. Among these current projects are studies that develop "interventions"
that reduce sun exposure in preschool children, as well as in high-risk
melanoma patients and their first degree relatives. Another project is
examining the psychosocial aspects of genetic testing and counseling for
people with a genetic risk of developing colon cancer.
Prevention also means addressing the psychosocial needs of patients with
cancer, with the goal of providing the best opportunities for regaining
health. "About 15 percent to 20 percent of patients have emotional or
psychological needs that have not been adequately dealt with," Gritz says.
"We have been so focused on disease treatment that those important elements
have traditionally been given lower priority."
In the Behavioral Research and Treatment Center, studies are carried out
on tobacco prevention and cessation and a range of other behavioral and
psychosocial research topics. These include social interaction, exercise and
sleep patterns. Other clinical research projects in Behavioral Science focus
on addressing sexuality following various cancers, discussing parenting post-
cancer treatment and studying the role of acupuncture, yoga and Chinese
medicine in the integrative medical treatment of cancer.
Finally, Gritz plans to tackle ways to prevent cancers associated with
obesity. Excess body weight is said to be responsible for about 10 percent of
breast and colorectal cancers, and up to 40 percent of kidney, esophageal and
endometrial cancers. "Finding ways to thwart the obesity epidemic that is
arising in this country will not only help prevent these cancers, but other
health issues such as heart disease and diabetes," she says.
Defining genes of risk and benefit
More than 80 percent of all lung cancer cases occur in people who have
smoked cigarettes, but what accounts for the fact that only a small percentage
of tobacco users will develop the disease? Why are some people more at risk?
Thats one of the central issues being researched at the Department of
Epidemiology, along with its corollary: why do some people with lung cancer
fare better with treatment than others?
Now expand these questions into other tobacco-associated cancers such as
those that occur in the bladder, kidney and esophagus, and to other non-
smoking related cancers such as melanoma, brain, prostate and lymphoma, and
that gives you an idea of the mission that Department Chair Margaret Spitz,
M.D., has undertaken since 1995. "Although an element of chance is likely to
play a role in the complex, multi-step process leading to cancer development,
there is mounting evidence that genetic factors also influence susceptibility
to cancer-causing exposures," she says.
Finding those genetic factors that determine risk of developing cancer, as
well as those that confer benefit from treatment, is the focus of the 213
employees in the department -- the largest in the division.
"The diversity of human beings is remarkable," Spitz says. "The fact that
some smokers develop lung cancer while others dont suggests that there are
differences among smokers in susceptibility to the cancer-causing compounds in
cigarettes.
"Individuals respond differently to environmental exposures," she says.
"They process chemicals differently, and they have a wide range of
susceptibility to the undesirable side effects of treatments. Such
differences could be explained by variation in our genes."
Humans have a series of overlapping mechanisms to deal with the
consequences of harmful environmental exposure, and these molecular pathways
are all under genetic control, she says. "In our genes are thousands of small
variations that may mean more -- or less -- production of an enzyme or protein
that contribute to our diversity and explain our different risks of developing
disease," Spitz says.
For example, her research has revealed a possible hereditary component to
nicotine addiction and an inability to quit, showing some smokers receive more
pleasure from nicotine than others because of genetic differences in the
brains dopamine reward pathway.
Another process under genetic control that could explain susceptibility is
DNA repair capacity. These systems help maintain the integrity of genes by
continually fixing the damage that occurs to DNA from exposure to harmful
chemicals as well as to the daily assault of cosmic X-rays and UV light. If
errors in this repair system occur, DNA damage can result in unstable genes
and an increased cancer risk.
"Some people just have better DNA repair function than others," Spitz
says. "If we can find out why, it may enable us to identify those at risk for
cancer at an earlier age and to tailor intervention therapies for each
individual."
Researchers in the department have studied variations in many DNA repair
genes to see how they affect lung cancer risk. In these published studies,
they report that patients with a variety of different cancers have
significantly poorer capacity to repair DNA damage compared to those who do
not develop the cancer.
Specifically:
* One finding demonstrated that individuals who dont eat enough dietary
folate (a vitamin found in some fruits and vegetables), and who had
genetic instability, are at much greater risk of developing bladder
cancer. Folate is crucial to DNA synthesis and repair, and cigarette
smoking (the major cause of the disease) puts this system under stress,
the researchers say.
The same genes that are implicated in cancer risk also may be involved in
prediction of patient outcome, Spitz says. Among recent discoveries are that:
* Patients with esophageal cancer who had the best treatment outcomes
were those that had gene variants that were less effective at
neutralizing the killing power of cancer treatments. For example,
patients treated with radiation treatment, who inherited less-effective
variants of a gene (XRCC1) that repairs DNA damage from radiation,
exhibited longer survival.
* People with more efficient DNA repair function who were given
chemotherapy, particularly platinum-based drugs like cisplatin, had a
lower overall survival rate than those with less efficient DNA repair.
While faulty DNA repair genes may put a person at risk for developing
cancer, they also may benefit them when that cancer is being treated, Spitz
says. "Such detailed genetic information can help us develop targeted
interventions depending upon individual risk, which will promote cancer
prevention and earlier detection as well as improve patient treatment and
outcome."
Currently, researchers in the Department of Epidemiology are studying more
than 3,000 patients diagnosed with lung, head and neck, bladder, kidney or
esophageal cancer. Similar approaches are ongoing for other cancers including
melanoma, glioma, lymphoma, and breast and prostate cancer. They ask these
patients questions relating to their smoking status, diet, occupation,
exposure to chemicals and family history, and then collect urine, blood and
tissue cells.
From these samples, they are applying novel molecular "assays," or tests
that gauge the biological importance of various genes or proteins.
Among the molecules being investigated in these assays are:
* Nicotine addiction genes;
* Gene variants involved in metabolism of chemicals, hormones and folic
acid;
* DNA repair genes;
* Agents that push cells to mutate, or change;
* Length of telomeres (protein caps that stabilize chromosomes);
* Genes that control the cell cycle;
* Genes involved in inflammation;
* Methylation (addition of methyl groups that destroy gene function); and
* Genes that control a cells "microenvironment."
The combined findings eventually will provide a molecular road map to risk
of cancer development as well as optimal cancer treatment. If oncologists
knew who would be most susceptible to cancer development, it may be possible
to use agents or behavior modifications as preventatives. If cancer does
develop, oncologists may be able to tailor treatment to an individuals own
genetic profile.
The department also has launched the first long-term effort to study
health outcomes and risk factors in the Mexican-American population in the
Houston metropolitan area, research paid for by philanthropy and tobacco
industry settlement funds. Over many years, the study aims to enroll more
than 100,000 Mexican-Americans in Texas, and to date more than 10,000 have
joined. The study will follow the residents and collect biological samples to
relate mortality and disease incidence to genetic, environmental and
occupational exposures, diet, other lifestyle factors and health behaviors.
A smaller five-year investigation, funded for $2.9 million by the National
Cancer Institute, will specifically look at patterns of smoking
experimentation and initiation in Mexican-American adolescents -- why they
begin smoking, how addiction sets in, what may help prevent their smoking and
how to help these young smokers quit.
"We may one day be able to answer the why me question -- why did I get
cancer -- or perhaps we might be able to prevent cancer from occurring at
all," Spitz says. "It wont happen overnight, or even in my lifetime, but
were definitely moving in the right direction."
A daily dose of prevention
Will the patient of tomorrow be given a cocktail of daily drugs that will
help prevent or reduce the chance of cancer developing?
This cocktail might include refined forms of anti-inflammatory drugs to
prevent colon cancer, trace minerals to protect against prostate cancer, or
proven versions of ancient remedies, such as turmeric spice for breast cancer
and cups of green tea daily to repress oral cancer.
M. D. Anderson is devoted to finding preemptive strikes -- ways to block
cancer from ever starting or from becoming clinically apparent. These efforts
are being spearheaded by Scott Lippman, M. D., chair of the Divisions
Department of Clinical Cancer Prevention, Levin and other researchers campus-
wide.
M. D. Anderson was among the first to look for agents that may help
prevent cancer -- some three decades ago, beginning with the innovative work
of Waun Ki Hong, M.D. -- and now is seen as a national leader in the field of
chemoprevention, Levin says.
Four of five classes of chemopreventive agents the National Cancer
Institute has said are promising and are "considered priority substances for
study" are being investigated here. 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 Hong, head of the Division of Cancer Medicine at M. D. Anderson and a
pioneer in the field. "Cancer doesnt begin with the appearance of a tumor,
just as cardiac disease doesnt 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."
Hong launched the first chemoprevention clinical trial of its kind when he
and a team of researchers demonstrated that smoking impaired the ability of
vitamin A and its chemical cousin, retinoids, to keep cells healthy. In the
early 1990s, they demonstrated that daily doses of retinoids could stop
precancerous growths in the mouth and oral cavity from turning into cancer.
They proved, for the first time, that cancer could be reversed. That work has
led to examining other formulas of retinoic acids and other, unrelated agents.
Current strategies of "chemoprevention" -- the use of natural or synthetic
substances to reduce the risk of developing cancer -- are less geared toward
preventing all cancer than toward preventing specific major cancers, Lippman
says.
"Great clinical strides have been made in breast, colorectal and prostate
cancer prevention," Lippman says. For example, he says that tamoxifen
(Nolvadex(r)) reduced breast cancer risk by 50 percent in the Breast Cancer
Prevention Trial, and finasteride (Propecia(r), Proscar(r)) reduced prostate
cancer risk by 25 percent in the Prostate Cancer Prevention Trial.
But men and women havent flocked to get prescriptions for either agent
because, as Lippman points out, these two large-scale trials indicated that
some serious side effects came along with preventive benefits. "This stand-
off between agent risks and benefits has raised a major focus of cancer
prevention -- tailoring interventions to specific groups of people.
"Efforts to identify people at a very high cancer risk and likely to
benefit from and not be harmed by particular agents will be crucial to the
future of cancer prevention," Lippman says. He leads an effort at M. D.
Anderson and several other cancer centers to understand prostate cancer risk
and how finasteride changed this risk in the Prostate Cancer Prevention Trial.
Other chemopreventive agents have proven to be effective. M. D. Anderson
researchers have found that:
* A low-dose baby aspirin proved effective as a modest colon cancer
chemopreventive. A randomized clinical trial of more than 1,000
participants found it reduced the number of precancerous polyps by 19
percent. Robert Bresalier, M.D., chair of the Department of
Gastrointestinal Medicine and Nutrition, helped lead this national
effort.
* Celecoxib, a non-steroidal anti-inflammatory drug (NSAID) known by the
trade name Celebrex(r), reduced the number of colon polyps in people
who have familial adenomatous polyposis (FAP), in which hundreds of
precancerous polyps form in the colon and rectum. The study, led
by researchers at M. D. Anderson and St. Marks Hospital, London, in
collaboration with the National Cancer Institute, led to federal
approval of Celebrex for FAP patients.
* Supplements of selenium and vitamin E unexpectedly reduced the
incidence of prostate cancer by up to two-thirds in trials testing them
for different cancers. These observations led to the ongoing
international Selenium and Vitamin E Cancer Prevention Trial (SELECT)
in more than 32,000 patients. M. D. Anderson leaders of SELECT include
Lippman and Elise D. Cook, M.D., who led the national effort to recruit
minority men, especially African-Americans, who have the highest risk
of prostate cancer in the world. Cooks successful campaign resulted
in the highest percentage of African-Americans ever recruited to a
large-scale cancer prevention trial.
* The spice curcumin (found in turmeric and curry powders) has shown
dramatic results in preventing cancer in animal studies, and has led to
clinical studies at M. D. Anderson with patients that have pancreatic
cancer or multiple myeloma. A trial with breast cancer patients is
expected to begin in 2005. Patients in these trials take curcumin
capsules daily.
A number of ongoing chemoprevention trials at M. D. Anderson are focusing
on reducing chronic inflammation, which has lately been associated with cancer
development. An agent of current interest in these investigations is
Celebrex, given its proven ability to prevent inherited colon cancer.
Celebrex works by blocking 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 bodys natural immune reaction to the cancer.
The precise way Celebrex, or any preventive agent, works is never simple,
however. Novel laboratory studies of Imad Shureiqi, M.D., at M. D. Anderson
show that 15-lipoxygenase-1 and related signaling pathways are at least as
important as COX-2 to the workings of Celebrex and other NSAIDs. "M. D.
Anderson is a world leader in research to better understand agent mechanisms,"
Lippman says. "And this research will hasten the arrival of safe and
effective preventive drugs into the hands of the people who need them."
Some of M. D. Andersons studies with Celebrex were halted after news that
the agents sister drug, Vioxx(r), was associated with an increase in
cardiovascular problems. Later, a slightly increased risk of cardiovascular
disease was also found in one of the polyp prevention trials using Celebrex.
Another multi-center international trial of Celebrex was also halted; this one
evaluated the role of the agent in preventing recurrence of precancerous colon
polyps and Levin is co-principal investigator.
After consultation with the National Cancer Institute, the following M. D.
Anderson studies investigating use of Celebrex as a chemopreventive have been
re-opened:
* An international trial in FAP looking at use of Celebrex combined with
eflornithine (DFMO), a drug used to treat African sleeping sickness, but
which is suspected of having anti-cancer properties. This study is led
by Patrick Lynch, M.D., in the Department of Gastrointestinal Medicine
and Nutrition.
* A clinical trial testing whether Celebrex can repair precancerous lung
damage in current and former smokers. Jonathan Kurie, M.D., in the
Department of Thoracic/Head and Neck Medical Oncology, is the principal
investigator.
* An international trial testing use of Celebrex in children who are
carriers of the mutated FAP gene, and who have little or no evidence yet
of polyps.
Hongs work also has led to a major international program of M. D.
Anderson in collaboration with Nordic investigators to prevent oral cancer
with two molecular-targeted drugs (Celebrex and erlotinib, also known as
Tarceva(r)) in people at extremely high risk of coming down with and dying
from this disease. A molecular marker, aneuploidy (an abnormal amount of
chromosomes in a cell), signals the risk of these people, "highlighting how
important accurate risk detection is for effective chemoprevention," Lippman
says.
As promising as some of the research has been, none of M. D. Andersons
chemoprevention experts, including Lippman and Levin, suggest that people take
a little Celebrex here, a dose of aspirin there, or swallow tablets of
curcumin with a dash of vitamin E as a way to "self medicate" against cancer.
They all stress 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. It will take decades, they
say, 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 didnt. "First, we must do no
harm," Lippman says.
Levin emphasizes that chemoprevention must not be substituted for other
important lifestyle habits such as avoiding tobacco, eating a nutritious diet,
exercising and managing body weight: "If you do these things and make sure
you are adequately screened, you may be able to reduce your odds of developing
cancer by 50 percent -- and that is a conservative estimate," he says.
"While we should be modest in claiming our work will lead to new
chemoprevention advances in the coming years, we have promising leads from the
laboratory that will enable us to conduct even better and more informative
trials in the future," Levin says.
This news release was issued on behalf of Newswise(TM). For more
information, visit http://www.newswise.com .
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