Cancer Biology & Therapy

ISSN: 1538-4047 (Print) 1555-8576 (Online) Journal homepage: http://www.tandfonline.com/loi/kcbt20

Cyclin D1 Connections to the Mitochondria

To cite this article: (2006) Cyclin D1 Connections to the Mitochondria, Cancer Biology &
Therapy, 5:9, 1058-1058, DOI: 10.4161/cbt.5.9.3337

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Published online: 30 Aug 2006.

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 [Cancer Biology & Therapy 5:9, 1051-1058, September 2006]; ©2006 Landes Bioscience
News
Celecoxib Reduces Size and
Occurrence of Adenomas
Unlocking Colon Cancer with Key of Prevention Study finds
that patients who took 400 milligrams of Celebrex® once daily
significantly reduced their incidence of potentially pre-malignant
colorectal polyps.
An international team of scientists reports that a single 400 milligram
daily dose of celecoxib, commonly called Celebrex® and manufac-
tured by Pfizer, significantly reduced recurrence of adenomas, or
pre-malignant colon tumors—within three years of previous adenoma
removal.
The New England Journal of Medicine on August 31, 2006 pub-
lished findings from the Prevention of Spontaneous Adenomatous
Polyps (PreSAP) study, involving more than 1,550 participants at
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107 sites in 32 countries on six continents. The study was led by
Nadir Arber, M.D., chair of the Integrated Cancer Prevention
Center and professor of medicine and gastroenterology at the Tel
Aviv Sourasky Medical Center and Bernard Levin, M.D., vice
president of Cancer Prevention and Population Sciences at The
University of Texas MD Anderson Cancer Center.
“Celecoxib 400 mg once daily significantly reduced colorectal
adenoma occurrence, with a greater effect on advanced adenomas,”
ON
.D
said Arber.
As excess amounts of the protein cyclooxygenase (COX-2) are
associated with adenomas and colon cancer, PreSAP researchers
CE
studied celecoxib—a selective COX-2 inhibitor—to prevent the
IEN
pre-cancerous lesions.
“There is no doubt that celecoxib is an effective agent in reducing
the size and occurrence of adenomas in patients with higher risks for
SC
colorectal cancer,” said Levin.
In the placebo-controlled, double-blind PreSAP trial, study leaders
BIO
randomly assigned participants to receive either a single 400-mg
dose of celecoxib (approximately 930 subjects) or a placebo (nearly
630 subjects). Subjects received colonoscopies after one and three
ES
years to detect potential pre-malignant tumors and their sizes, as well
the overall adenoma burdens for participants. All polyps were
ND
removed and examined by study pathologists.
At the conclusion of the trial, the cumulative adenoma rate for
the celecoxib study group was 33.6%, while the cumulative rate of
LA
adenoma development in the placebo group was 49.3% (a 36%
reduction). Celecoxib administration was associated with a 50%
06
reduction in larger, potentially more dangerous adenomas.
“Unlike the recent Adenoma Prevention with Celecoxib (APC)
20
trial, we did not find a statistically significant increase in cardiovas-
cular risk associated with the use of 400 mg of celecoxib once daily,”
©
said Levin. “That said, because of the significant cardiac side effects
seen in the APC study, further cardiovascular research on the use of
all anti-inflammatory drugs, such as Celebrex®, Aleve® and Motrin®,
as chemoprevention tools is warranted.
“Low dose aspirin also has been shown to reduce adenoma
formation in individuals with a prior history of polyps and has the
potential to decrease cardiovascular disease risk,” said Levin.
“However, its use is associated with an increased risk of upper-
gastrointestinal bleeding and stroke.”
www.landesbioscience.com Cancer Biology & Therapy
The three-year APC study, with more than 2,000 participants,
sought to reduce adenoma size and occurrence through the use of
celecoxib. In the study, APC researchers administered celecoxib
twice daily at either 200 mg or 400 mg doses. The study showed that
the drug nearly doubled cardiovascular risk to participants.
“While our findings are exciting in that they suggest great poten-
tial for reducing adenoma formation in patients with high risk for
colorectal cancer, we’ve scratched the surface with the PreSAP trial,”
said Levin. “Until these impressive prevention results are realized
with lessened cardiovascular risk, we cannot advise celecoxib routinely
as a tool for colon cancer prevention. Once daily dosing may provide
.
E
an important insight into ways to diminish the untoward cardiovas-
UT
cular effects of celecoxib.”
Levin has served as a consultant for Pfizer, which provided grant
RIB
A Prolyl Hydroxylase Contributes
support for the PreSAP trial. These arrangements are managed by
MD Anderson in accordance with its conflict of interest policies.
to Anti-Angiogenic Effect of p53
IST
D
OT
Angiogenesis, or the growth of new blood vessels, is an important
naturally occurring process in the body. As with normal tissues,
tumors rely on angiogenesis to supply them with the oxygen and
nutrients they need for growth. This understanding has led
researchers to explore antiangiogenic therapies for the suppression of
tumor growth. Among the most potent known inhibitors of tumor
angiogenesis are C-terminal fragments of collagen, one of the most
abundant proteins in the body. However, it was unknown how
production of antiangiogenic fragments from full-length collagen
was controlled.
Now, researchers at the University of Massachusetts Medical
School have demonstrated a connection between p53, a commonly
known tumor suppressor, and the production of antiangiogenic
collagen fragments.
Dubbed the “guardian of the genome,” p53 is the body’s primary
tumor suppressing protein. Involved in regulating the response of
cells to stress, p53 has the ability stop cells from dividing when they
are damaged and, in some cases, to encourage such cells to destroy
themselves via programmed cell death, or apoptosis. In the continuing
efforts to understand how p53 influences cell death, scientists have
found that the presence of p53 in tumors also influences angiogenesis.
In their paper, “p53-Mediated Inhibition of Angiogenesis
through Upregulation of a Collagen Prolyl Hydroxylase,” published
in the August 18, 2006 issue of Science, UMMS scientists, led by
Howard Hughes Medical Institute Investigator Michael R. Green,
M.D., Ph.D., the Lambi and Sarah Adams Chair in Genetic
Research and professor of molecular medicine and biochemistry &
molecular pharmacology, sought to define the mechanisms by which
p53 influences the regulation of angiogenesis. In doing so, Dr.
Green and colleagues identified a gene-alpha II collagen prolyl
hydroxylase [alpha(II)PH]-that is not only stimulated by p53 but is
also necessary for the p53-mediated production of antiangiogenic
collagen fragments. Remarkably, when alpha(II)PH was delivered to
mice, tumor growth could be dramatically inhibited. These findings
reveal both a genetic and biochemical linkage between the p53
1051
 News
tumor suppressor pathway and the production of antiangiogenic
collagen fragments, as well as new strategies for combating cancer.
The University of Massachusetts Medical School, one of the
fastest growing medical schools in the country, has built a reputation
as a world-class research institution, consistently producing noteworthy
advances in clinical and basic research. UMass Medical School and
its clinical partner, UMass Memorial Health Care, attract more than
$174 million in research funding annually, 80% of which comes
from federal funding sources. Research funding enables UMass
researchers to explore human disease from the molecular level to
large-scale clinical trials. Basic and clinical research leads to new
approaches for diagnosis, treatment and prevention of disease.
Chromosome 8q24 Linked to
For more infformation, contact: Kelly Bishop; Tel.: 508.856.2000
Elevated Prostate Cancer Risk in
African Americans
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Researchers from Dana-Farber Cancer Institute and Harvard
Medical School have found a region of the human genome that
accounts for the higher risk of prostate cancer in black Americans.
Matthew Freedman, M.D., a Dana-Farber researcher and lead
author of a paper in the August 21, 2006 online version of the
Proceedings of the National Academy of Sciences, said the genetic factor
lies in a group of genes located on a region of the eighth human
chromosome.
Depending on their ancestry, black men may have inherited the
DNA segment (actually, there are two copies of it) from lineage
going directly back to Africa, or from European ancestors, or from
both. The data indicate that those who have inherited this chromo-
somal region from African rather than European ancestors have a
higher prostate cancer risk.
“This is one of the first times that a genetic risk factor has been
identified in the general population that contributes to prostate
cancer risk, and which may give us an insight into the underlying
biology of the disease,” said Freedman, who is also affiliated with
Harvard Medical School and the Broad Institute of MIT and
Harvard.
Freedman and his collaborators are carrying out further work to
pinpoint which of nine genes within the African-derived DNA
segment, designated 8q24 on a “map” of the chromosomes, actually
causes the cancer susceptibility. “This could give us an insight into
molecular pathways that trigger the development of prostate cancer,
and what therapies you might use in treating it,” Freedman said.
Last May, an Icelandic gene-hunting company first announced
the discovery of a genetic risk factor that explained the prostate
cancer disparity. The genetic variant identified by the company,
deCODE Genetics, is physically located in the same region described
by the new report, but is not itself the cause of the heightened cancer
susceptibility, say the Dana-Farber and Harvard scientists.
David Reich, Ph.D., senior author of the PNAS report, said,
“This paper is important because it confirms what deCODE found:
our two groups have independently converged on the same region.
I’m absolutely convinced that this explanation for the difference in
prostate cancer susceptibility is real.”
The results of both studies show that the genetic risk factor operates
more strongly at younger ages, and becomes less marked at older
1052 Cancer Biology & Therapy
ages. Black men who inherited the DNA segment from African
ancestors and are younger than 55 have a 2.3-fold higher risk of
developing prostate cancer. However, by age 72, the difference in
risk declines to 1.4 times higher.
Reich, Freedman and their co-authors used a powerful technique
called “admixture mapping” to focus the search through 23 pairs of
chromosomes, carrying a total 3.5 billion letters of genetic code—
the genome—to find disease-susceptibility genes. In a multi-ethnic
sample of patients, according to the “admixture” concept, it is likely
that near a disease-causing gene there will be a marked abundance of
DNA from the population that has the greater risk of developing the
disease.
In this case, the technique enabled scientists to test African
American prostate cancer patients, as well as groups without the
disease, and noticed a region on Chromosome No. 8 with an enrich-
ment of DNA inherited from African, as opposed to European,
lineages. That was a sign that the genetic factor for increased prostate
cancer susceptibility was in the neighborhood.
The result was the identification of a region comprising 3.8
million bases, or letters of the genetic code, associated with elevated
risk of prostate cancer. It is within those 3.8 million letters, believed
to contain nine genes as well as a large amount of DNA extraneous
to the genes, that the causative genetic difference is expected to be
found.
In addition to Freedman and Reich, authors include Brian E.
Henderson, M.D., of the University of Southern California, and
David Altshuler, M.D., Ph.D., of the Broad Institute and Harvard
Medical School.
The research was supported by grants from the National
Institutes of Health.
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal
teaching affiliate of the Harvard Medical School and is among the
leading cancer research and care centers in the United States. It is a
founding member of the Dana-Farber/Harvard Cancer Center,
designated a comprehensive cancer center by the National Cancer
Institute.
MC1R Variants May Contribute to
For more information, contact: Bill Schaller or Richard Saltus; Tel.: 617.632.4090
Melanoma Risk
People with red hair, light skin or freckles are more likely than
others to develop the deadliest skin cancer—malignant melanoma.
A single gene greatly influences these traits. A new study now
demonstrates that the same gene is especially likely to put individuals
at risk for a particular type of melanoma that most often occurs in
one’s 40s or 50s—regardless of whether the gene bearers are light-
complexioned.
Researchers—led by Boris Bastian, M.D., of the UCSF
Comprehensive Cancer Center and by Maria Teresa Landi, M.D.,
Ph.D., from the National Cancer Institute—report in the July 28,
2006 issue of Science that being born with variations in a gene called
MC1R results in an especially high susceptibility to a genetically
distinct form of melanoma. Like freckles, variants in the MC1R
gene are relatively common among whites in comparison with the
entire world population.
The Science study highlights again how important it is for the
fair-skinned to avoid sunburn. The results also led the study authors
2006; Vol. 5 Issue 7
 News
to the suspicion that susceptibility to damaging mutations in a gene
called BRAF may peak before adulthood in individuals born with
MC1R variants.
The MC1R gene is the blueprint for a protein found on special-
ized skin cells called melanocytes. Variants cause melanocytes to
make less of a protective pigment called melanin in response to UV
exposure. However, MC1R variants may contribute to melanoma
risk beyond their effects on pigmentation—even dark-skinned or
easily tanning persons with MC1R variants may be at increased risk.
DIFFERENT TYPES OF MELANOMA
Only recently have researchers and clinicians begun to appreciate
that there are different types of melanoma. This new recognition is
due in large part to Bastian, a dermatologist and skin pathologist
who specializes in discriminating among benign and malignant skin
growths.
Last November, Bastian and colleagues reported in the New
England Journal of Medicine there are at least four types of
melanomas. The two most common forms of the malignancy in the
United States are associated with exposure to the sun’s UV rays. In
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the Science study, Bastian and colleagues found that people with
MC1R variants are most susceptible to a type of melanoma that
occurs most often among people in their 40s and 50s, and that is
found most often on the trunk, arms and legs—skin that normally
does not show signs of chronic skin damage associated with age and
long-term UV exposure.
These melanomas usually have acquired BRAF mutations, which
are abnormalities that help drive tumor growth. Drugs are being
developed that specifically target tumors driven by BRAF mutation.
However, at this time, melanomas—with or without BRAF muta-
tions—are very difficult to treat successfully when not detected early.
Another common form of melanoma occurs most often later in life
on chronically damaged skin—often on the face or neck.
To conduct the study reported in Science, the researchers examined
genes and tissue from 197 white melanoma patients from northern
Italy and the United States, with and without inherited variant
MC1R genes.
Among patients with melanomas that arose on skin that had not
been chronically damaged, individuals who had inherited two copies
of variant MC1R genes had tumors with BRAF mutations in more
than 80% of cases. BRAF mutations were present in only 30% of
melanomas that arose on skin that had not been chronically damaged
among individuals with two copies of the common, “wild-type” MC1R.
POSSIBLE WINDOW OF VULNERABILITY DURING CHILDHOOD
Not only the amount of UV exposure, but also the age at which
one is exposed might be an important component of risk, Bastian
suggests.
“If you put it all together, it seems likely that MC1R plus UV
light may make young children very vulnerable to developing these
BRAF mutations,” he says.
Consistent with this idea is the fact that melanomas often develop
from moles, and a majority of moles arise during childhood and
adolescence, according to Bastian. The moles people are born with,
Bastian and colleagues have found, never show BRAF mutations.
The moles that arise later often have BRAF mutations. Melanomas
typically take many years to develop. The earlier average age of diag-
nosis for BRAF-harboring melanomas on skin not chronically
www.landesbioscience.com Cancer Biology & Therapy
exposed may reflect a childhood window of vulnerability that
Notch2 and CDK5 as Therapeutic
occurred decades earlier.
The best advice for the fair-skinned remains—stay out of the sun.
Targets
The following studies by Johns Hopkins researchers describe two
new potential targets for cancer drugs, one that takes aim at the
beginning of the tumor growth process and origins of cancer cells
and the other at the process of tumor spread. Reports on the work,
published in the August 1, 2006 issue of Cancer Research, describe
experiments with mice and cell cultures that could lead to new treat-
ments for childhood brain tumors and adult prostate cancers.
RESEARCHERS TARGET CELLS THAT CAUSE BRAIN CANCER
Building on previous research linking a common childhood brain
cancer called medulloblastoma with high levels of the Notch2 gene,
a team led by Charles Eberhart, M.D., Ph.D., is exploiting Notch2
gene products known to regulate brain stem-cell growth and survival.
The new studies provide the first hint that a class of drugs, called
gamma secretase inhibitors, which block Notch proteins and currently
are being developed for Alzheimer’s disease, specifically kills stem
cells responsible for creating and sustaining a brain tumor.
“Drugs that we typically use to treat cancer don’t seem to kill
tumor stem cells,” says Eberhart, associate professor of pathology
and oncology, and after the stem cells survive an onslaught of
chemotherapy and radiation, they are left to regrow new tumors.
Gamma secretase inhibitors appear to overcome this barrier.
Eberhart and postdoctoral fellow Xing Fan, M.D., Ph.D., treated
medulloblastoma cell cultures for 48 hours with a gamma secretase
inhibitor and found that tumor growth slowed. Closer inspection of
the types of cells in the culture revealed that the cancer’s stem cells
were almost completely eliminated by the drug, but remained in
drugless cultures.
Intrigued, the researchers injected the drugged and drug-free
cultured cells into mice. All 24 control mice with cells not treated
with the Notch-blocking drug grew large tumors. Mice that received
cells previously treated with the drug fared much better. Only two of
eight mice in this group grew very small tumors—less than one-tenth
the size of control tumors.
“Medulloblastoma stem cells have much higher Notch gene activity
than other cells in the tumor, which may be why the stem cells die
first. They are more dependent on the Notch pathway, and blocking
it causes severe problems,” Eberhart explains.
Although the stem cells are a very small percentage of the entire
tumor—approximately 1%—other researchers have identified
heavy-duty transporters on their cell surfaces that may pump out
chemotherapy drugs and cause cancers to become treatment-resistant.
Eberhart and Fan are continuing laboratory studies to select an
appropriate gamma secretase inhibitor for clinical trials.
This study was funded by the Children’s Cancer Foundation of
Baltimore, MD. Additional authors include William Matsui, Leila
Khaki, and Duncan Stearns of Johns Hopkins; and Jiong Chun and
Yue-Ming Li of Memorial Sloan-Kettering Cancer Center.
1053
 News
ENZYME LINKED TO PROSTATE CANCER SPREAD
Johns Hopkins Kimmel Cancer Center scientists have found that
an enzyme, normally associated with the nervous system, appears to
control deadly spread in prostate cancer. Blocking the enzyme, called
CDK5, could prevent disease spread in high-risk patients and make
metastatic cells more susceptible to chemotherapy.
“Cancer cells must be able to ‘crawl’ out of the primary tumor in
order to spread,” says Barry Nelkin, Ph.D., professor of oncology,
who notes that the cell’s mobility is controlled by activation of the
CDK5 enzyme. The enzyme alters a cell’s inner skeleton, allowing it
to change shape and move to invade other tissues.
Says Nelkin, cancer cells also activate CDK5 to reduce the number
of “sticky” molecules coating its surface and loosen the bonds to
neighboring cancer cells. Once a cancer cell pulls free, it can migrate
to other areas of the body via the bloodstream and establish poten-
tially lethal spread. High levels of active CDK5 were found in
prostate cancer cells, as well as melanoma and thyroid, adrenal,
pancreatic and small cell lung cancers.
Using mice with a form of prostate cancer that spreads to the
lung, the researchers implanted genetically modified tumors that
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blocked the CDK5 enzyme. Mice with CDK5-free tumors had a
79% reduction in the number of metastatic lung lesions.
The researchers will continue studies to determine the role of
CDK5 in other cancers and development of a CDK5 enzyme-
blocker suitable for humans.
This research was funded by the National Cancer Institute and
Patrick C. Walsh Prostate Cancer Research Fund. Authors include
Christopher J. Strock, Jong-In Park, Eric K. Nakakura, G. Steven
Bova, John T. Isaacs, and Douglas W. Ball of Johns Hopkins.
CALM-AF10 Fusion Gives Clues to
For more information, contact: Vanessa Wasta; Tel.: 410.955.1287
Disregulated HoxA5 and Leukemia
Development
New research from the University of North Carolina at Chapel
Hill has identified a molecular process in cells that is crucial to the
development of two common leukemias.
The findings help explain how fundamental cell processes go
awry during cancer development and represent a first step toward
new, targeted treatments for leukemia.
Acute lymphoblastic leukemia (ALL) and acute myeloid
leukemia (AML) leukemias develop when certain chromosomal
abnormalities disrupt the genes that control blood cell formation.
Without the proper instructions from these genes, blood cells
produced by bone marrow never fully mature; these immature cells,
which can’t carry vital nutrients or fight infection, then flood the
body.
The researchers showed how a fusion of proteins created by
flawed chromosomes can trigger leukemia development. The study
also identified an enzyme’s important role in this process.
The results were published online August 20, 2006 in the journal
Nature Cell Biology.
The research was led by Dr. Yi Zhang, professor of biochemistry
and biophysics in the UNC School of Medicine and a Howard
Hughes Medical Institute Investigator. Zhang is also a member of
1054 Cancer Biology & Therapy
the UNC Lineberger Comprehensive Cancer Center. The work was
supported by grants from the National Institutes of Health.
The study examined chromosomal translocation, in which a frag-
ment of a chromosome breaks off and joins another. Chromosomes
are the cellular structures that carry DNA. Translocation along chro-
mosomes can result in the generation of fusion proteins that often
“misregulate” specific genes, including genes that can cause
leukemia, and is a common cause of leukemia, Zhang said.
The most common chromosome translocations found in
leukemia patients involve the mixed lineage leukemia gene, MLL.
One of the fusion proteins that partners with MLL in leukemia is
AF10.
AF10 has been shown to fuse with another protein, CALM, in
patients with acute lymphoblastic leukemia or acute myeloid
leukemia. But it has been unclear whether that fusion could cause
leukemia, and little is known about how this CALM-AF10 fusion
may lead to the disease, Zhang said. “Results from this study provide
important insights into these questions,” he said.
Zhang and his colleagues showed that the CALM-AF10 fusion is
“necessary and sufficient” for cellular transformation to leukemia in
a mouse model of the disease. They also discovered that the fusion
overactivates (also called upregulation) the gene HoxA5. Moreover,
upregulation of the HoxA5 gene is necessary for cellular transforma-
tion to leukemia, the study shows.
Overactive Hox genes are known to play a role in cancer, Zhang
said. “In mammals, Hox genes play an important role in embryonic
development. They help set the developmental pattern. They also
play a role in cancer. That’s why their expression must be tightly
controlled.”
The researchers also identified an enzyme, hDOT1L, as important
for upregulating gene expression by the CALM-AF10 fusion protein.
This finding builds on earlier work by the Zhang laboratory involving
another fusion protein, MLL-AF10, and the enzyme’s upregulation
of the Hox gene HoxA9.
Having demonstrated the role of hDOT1L in leukemia develop-
ment of two different fusion proteins, the Zhang lab is exploring the
possibility of developing drugs that target the hDOT1L enzyme.
“Understanding the molecular mechanism underlying leukemia
development will certainly help in this endeavor, Zhang said.
UNC co-authors include postdoctoral researchers Drs. Yuki
Okada and Qi Jiang, and Lineberger Cancer Center researcher
Lishan Su. Other authors are Dr. Margot Lemieux and Dr. Lucie
Genomic Profiling of Lung Cancer
Jeanotte from the Center for Research at Hotel-Dieu Medical Center
of Quebec, in Montreal.
Predicts Recurrence Suggesting
Which Patients May in the Future
Benefit From Aggressive Treatment
Duke University Medical Center scientists have developed the
first-ever genomic test to predict which patients with early-stage lung
cancer will need chemotherapy to live and which patients can avoid
the toxic regimen of drugs.
The test has the potential to save thousands of lives each year by
recommending chemotherapy for patients who are currently advised
2006; Vol. 5 Issue 7
 News
against it, said the test’s developers at Duke’s Institute for Genome
Sciences & Policy.
The test’s promising results have initiated a landmark multi-cen-
ter clinical trial, to be led by Duke investigators next year. Patients
with early-stage non-small cell lung cancer, the most common and
fatal form of cancer, will receive the genomic test and its results will
determine their treatment.
The new test, called the Lung Metagene Predictor, scans thousands
of genes to identify patterns of gene activity in individual tumors
that indicate a patient is likely to suffer a recurrence of disease.
Recurrent tumors are typically fatal, so identifying at-risk patients is
critical to properly treating them, said the Duke researchers.
“Using the unique genomic signatures from each tumor, our new
test predicted with up to 90% accuracy which early-stage lung cancer
patients would suffer a recurrence of their cancer and which patients
would not,” said Anil Potti, M.D., an assistant professor of medicine
and lead author of the study. “We now have a tool that can be used
to move these high-risk patients from the ‘no chemotherapy’ group
into the aggressive treatment group.”
The researchers published their findings in the August 10, 2006,
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issue of the New England Journal of Medicine. The research was
funded by the National Institutes of Health.
The genomic test can theoretically apply to any cancer, but the
Duke team focused its effort on lung cancer because the survival rate
is just 15%. Lung cancer now kills more Americans each year than
breast, prostate and colorectal cancers combined. But toxic
chemotherapy drugs are prescribed only to patients with relatively
large and aggressive tumors.
Early-stage patients—those with small, stationary tumors—are
considered at low risk of recurrence. Hence, they only receive surgery
but not chemotherapy. The dilemma, said Potti, is that a third or
more of early-stage patients who appear to be at low risk will experience
a recurrent tumor.
“Until now, there simply has been no way to identify the 30% to
40% of early-stage lung cancer patients who would experience a
recurrence,” Potti said. “Now, with our test, we can say with confidence
that we can identify this group of patients so they can be treated
accordingly.”
The upcoming trial is the first to use a genomic test to select
treatment options for individual lung cancer patients, said David
Harpole, M.D., a professor of thoracic surgery at Duke and principal
investigator of the upcoming clinical trial. The trial, to begin within
six months, will enroll more than 1,000 patients at multiple centers
in the United States and Canada.
“If we can use the test to increase patient survival by even 5%, we
would save 10,000 lives a year,” Harpole said.
The Duke researchers developed the test by analyzing the activity
of genes from early-stage lung cancer patients whose disease out-
comes were known. The Duke scientists then validated the genomic
test in 129 patients by comparing the test’s predictions with the
patient’s actual outcomes. The test predicted their risk of recurrence
with 90% accuracy, the study showed.
If proven to be effective in the clinical trial, the test will replace
the current method of assessing risk, which is imprecise and provides
only a broad estimate of a patient’s risk, said Joseph Nevins, Ph.D.,
a professor of molecular genetics at Duke and senior author of the
study being reported.
Physicians now assign each patient to a clinical “stage” based on
the size of the patient’s tumor, whether it has invaded lymph nodes
and whether it has spread to other organs. They use this staging
www.landesbioscience.com Cancer Biology & Therapy
method to prescribe the best treatment options. But staging param-
eters are general, at best, and do not accurately define who should
receive chemotherapy, Nevins said.
“Instead of placing all patients with small tumors in the same
early-stage category, as physicians currently would do, we can now
assess their risk based on the tumor’s genomic profile,” Nevins said.
“The current system of ‘staging’ lung cancer tumors will eventually
become obsolete.”
To employ the test, physicians take a sample of the tumor as it is
removed during surgery. They extract its “messenger RNA,” which
represents the activity of thousands of genes in the tumor. Messenger
RNA translates a gene’s DNA code into proteins that run the cell’s
activities. Hence, it is a barometer of a gene’s activity level inside the
cell.
Scientists label the messenger RNA with fluorescent tags. The
fluorescent RNA is then placed on a tiny glass slide, called a gene
chip. There, it binds to its complementary DNA sequence on the
gene chip.
When scanned with special light, the fluorescent RNA emits a
telltale luminescence that demonstrates how much RNA is present
on the chip—and thus which genes are most active in a given tumor.
The physicians then use a rigorous statistical analysis to assess the
relative risk of large grouping of genes, called metagenes, which have
similar characteristics.
The test generates a risk “number” for each patient. If their risk
exceeds 50%, the patient is advised to get chemotherapy.
“This new genomic test is a clear example of personalized medicine,
where we use the unique molecular characteristics of each patient’s
tumor to guide treatment decisions,” said Geoffrey Ginsburg, M.D.,
Ph.D., a professor of medicine and co-author of the study.
Eventually, physicians will use genomic tests not only to predict
patient outcomes, but also to select the individual drugs that will
best match a tumor’s molecular makeup, Ginsburg said.
Other collaborators on the study being reported include, from
Duke, Sayan Mukherjee, Holly Dressman, Andrea Bild, Rebecca
Petersen, Jason Koontz, Michael Kelley and Mike West; Robert
Cyclin D1 Connections to the
Kratzke of the University of Minnesota; and Mark Watson of
Washington University in St. Louis.
Mitochondria
Scientists at Jefferson Medical College and the Kimmel Cancer
Center at Thomas Jefferson University in Philadelphia have found
how a gene can dim the power production in the cell and in turn
scale up its cancer-producing activities.
Two new studies provide stunning evidence suggesting that cyclin
D1—which is found in up to eight times normal amounts in half of
all breast cancers—can cause a shift in the cancer cell’s metabolism,
changing its focus from energy production to proliferation. The
findings, they say, may point to new therapeutic strategies against
cancer.
Reporting in July, 2006 in the journal Molecular and Cellular
Biology, Kimmel Cancer Center director Richard G. Pestell, M.D.,
Ph.D., Professor and Chair of the Department of Cancer Biology at
Jefferson Medical College, and colleagues showed for the first time
that cyclin D1—normally involved in promoting cell division inhibits
the size and activity of the cell’s energy-making mitochondria.
1055
 News
In a separate report in August, 2006 in the Proceedings of the
National Academy of Sciences (PNAS), Dr. Pestell and a different
team identified the mechanism behind cyclin D1’s mitochondrial
takeover. The research, taken together, shows that the inhibition
leads to increased proliferation of cancer cells.
“From the cancer cell’s point of view, the inhibition allows the
cell to shift its biosynthetic priorities—it allows it to shift from
making mitochondria themselves to synthesizing DNA and making
the cell proliferate,” says Dr. Pestell.
“Cyclin D1 shifts the individual cell’s metabolism away from
making mitochondria and towards cellular proliferation and the
various genes involved in promoting such proliferation,” he says.
The mitochondria often are called the “powerhouse” of the cell
because they produce about 90% of the body’s energy. They are
located in the cytoplasm outside of each cell’s nucleus.
Dr. Pestell notes that scientists have long suspected a link
between mitochondrial malfunction and cancer, and since 1930
have known about such a change in metabolism when the cell turns
cancerous. But the mechanisms haven’t been well understood. When
cells turn cancerous, they shift the way they metabolize glucose and
other substrates. The researchers believe that their findings about
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cyclin D1 are part of such a mechanism. “These changes were
observed previously,” he says.
“Now we know that the same factor that is involved in causing
breast cancer also directly causes a metabolic shift.”
I. Bernard Weinstein, M.D., Frode Jensen Professor of Medicine
at Columbia University, notes that the 1930 discovery that the
function of mitochondria is often impaired in cancer cells has
remained unexplained and cancer research has been mainly focused
on abnormalities in the function of genes in the nucleus of cells. The
work by Dr. Pestell’s group “provides novel insights into how these
two types of abnormalities in cancer cells might be related.”
In the PNAS publication, Dr. Pestell’s team found that a protein,
nuclear respiratory factor-1 (NRF-1), regulates a gene called mtTFA
and is essential for mitochondrial function. To make mitochondria,
then, NRF-1 turns on mtTFA, which then activates genes that
produce mitochondria. Cyclin D1 inactivates NRF-1, halting
production.
“This discovery advances our understanding of the behavior of
cancer cells and may suggest new types of cancer therapy,” Dr.
Weinstein says.
Dr. Pestell notes that such metabolic changes should leave the
cancer cell vulnerable. “We’d like to link that change in metabolism
to therapies,” he says. “We’ve been able to prove that we can see
changes in metabolism in the breast, and we should be able to target
that change and kill the cancerous cells.” He explains that specialists
can image tumors based on changes in metabolism.
The results could also “provide a mechanism for targeting the
mitochondria, rather than the nucleus,” he says, noting that cancer
drugs usually target nuclear genes. “Importantly, they provide a
direct link between the mitochondria and the nucleus—one gene
regulating both compartments of the cell. We didn’t know what
coordinated both functions. This shows both are functionally linked
by a common gene.”
“If we have therapies that target changes in metabolism, it allows
us to develop therapies selective for the cancerous cells only,” says
Dr. Pestell.
1056 Cancer Biology & Therapy
BRCA1 and BRCA2 Mutations and
Cancer Risk in African American
and Caucasian Women
Aug. 15, 2006—A large, population-based, multicenter study led
by researchers at Fred Hutchinson Cancer Research Center provides
the clearest picture yet of the prevalence and predictors of mutations
in the breast-cancer susceptibility genes BRCA1 and BRCA2 among
women in the general population.
Most research on these genes in relation to breast and ovarian
cancer has focused on rare, high-risk families and younger women.
Until now, the impact of these genetic mutations among women in
the population at large—particularly among African-Americans and
those age 45 and older—has been understudied and, as a result,
poorly understood, according to lead investigators Kathleen E.
Malone, Ph.D., Elaine A. Ostrander, Ph.D., and colleagues, whose
findings appeared in the August 15, 2006 issue of Cancer Research.
“Prior studies focused on high-risk families and younger,
Caucasian women. Clarifying the prevalence and predictors of these
mutations in a wider spectrum of the general population, including
understudied groups like African-Americans and older women, is
important and long overdue,” said epidemiologist Malone, a member
of the Hutchinson Center’s Public Health Sciences Division.
In a study of more than 2,300 African-American and Caucasian
women with and without breast cancer from five U.S. metropolitan
areas, the researchers found that among breast-cancer cases overall,
2.4% and 2.3% carried mutations in BRCA1 and BRCA2, respectively.
BRCA1 mutations were significantly more common in white
(2.9%) versus black (1.4%) cases and in Jewish (10.2%) versus non-
Jewish (2.0%) cases. BRCA2 mutations were slightly more common
in black (2.6%) versus white (2.1%) cases.
The researchers also examined predictors of carrying a mutation
in either gene. The strongest and most significant predictors of carrying
a BRCA1 mutation were diagnosis before age 45 in the case herself
or in a relative, ovarian cancer in a relative and Jewish ancestry.
Predictors of BRCA2 mutation status included early age at diagnosis
in the case herself or in her relatives.
“These data are critical for identifying women who would most
benefit from genetic testing,” said geneticist Ostrander, formerly
head of the genetics program at the Hutchinson Center who is now
chief of the Cancer Genetics Branch at the National Human
Genome Research Institute.
A unique aspect of the study was the inclusion of African-
American women, Malone said. “Until now there have been very
little data regarding BRCA-carrier status in African-American
women. The absence of data on such women could lead to the
misconception that they are less likely to carry a mutation in one of
these genes. In fact, this study confirms that African-American
women carry mutations in broadly similar proportions to Caucasian
women,” she said.
Among breast-cancer cases with a family history of ovarian cancer,
14% were found to carry a BRCA 1 mutation. Among those who
had a family history of both breast and ovarian cancer, 27% carried
a BRCA 1 mutation.
2006; Vol. 5 Issue 7

While the population-based study confirmed what previously has
been observed in high-risk families—that BRCA mutations are
indeed most common in younger women with breast cancer—the
research also provided the first direct evidence that women diagnosed
with breast cancer later in life also can be mutation carriers, although
the probability decreases with age. The prevalence of BRCA mutations
fell to about 2% among breast-cancer cases diagnosed at ages 60 to 64.
According to the National Cancer Institute, more than 192,000
U.S. women are diagnosed with breast cancer every year. Among
women who carry a mutation in BRCA1 or BRCA2, an estimated
36% to 85% (360 to 850 women out of 1,000) will get breast cancer.
In addition, women with breast cancer who carry a mutation also
face an increased risk for developing a second breast cancer or ovarian
cancer.
“While the primary thrust of this research was to identify predictors
of carrying the high-risk mutations and to clarify mutation preva-
lence in understudied groups, the relatively small proportion of cases
found to carry a mutation serves as a continued reminder that the
majority of women with breast cancer, even those with a positive
family history, do not carry mutations in these genes,” said Malone,
who is also a research professor of epidemiology at the University of
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Washington School of Public Health and Community Medicine.
For the study, Malone, Ostrander and colleagues examined the
frequency and predictors of BRCA1 and BRCA2 mutations in 1,628
women with breast cancer and 674 women without the disease. The
women ranged in age from 35 to 64 and were participants in the
National Institute of Child Health and Human Development’s
Women’s Contraceptive and Reproductive Experiences (CARE)
Study, which involved women from the Seattle, Los Angeles,
Atlanta, Detroit and Philadelphia metropolitan areas.
The research team included investigators from the University of
Southern California in Los Angeles; Wayne State University in
Detroit; the University of Pennsylvania in Philadelphia; Bay State
Medical Center in Springfield, Mass.; the National Cancer Institute
(NCI); the National Institute of Child Health and Human
Development (NICHD); and the Centers for Disease Control and
Prevention.
The NICHD and NCI funded the research.
For more information, contact: Kristen Woodward; Fred Hutchinson Cancer Research Center; Tel.: 206.667.5095; Email:
Burnham Expands to Sunshine State
kwoodwar@fhcrc.org
The Burnham Institute for Medical Research (Burnham), a
California-based, non-profit medical research institute, announced
on August 23, 2006 its intention to establish a major research facility
in Orlando, Florida, which will provide the organization with
bicoastal operations.
The Burnham will develop its Florida site through a unique
partnership with the State of Florida, Orange County, the City of
Orlando, the University of Central Florida, the University of
Florida, the Tavistock Group, and Florida’s philanthropic community.
“We are enormously grateful to the people of Florida for their
generous support of our medical research efforts and to Governor
Jeb Bush and the Florida State Legislature for their vision”, said Dr.
John Reed, President & CEO of Burnham Institute for Medical
Research. Dr. Reed is also an Associate Editor of Cancer Biology and
Therapy. “By providing the financial means for our expansion into
Florida, together with increased investments in its public universities,
www.landesbioscience.com
News
Governor Jeb Bush and Dr. John Reed announce Burnham's planned
expansion in Orlando, Florida. Press conference, Tallahassee. Photo courtesy
the Governor's office.
the State’s leadership is laying a superb foundation for growth of
biotechnology in Florida. This exceptional partnership will allow us
to drive our scientific discoveries more rapidly toward clinical proof
of concept, narrowing the gap between discovery and the development
of new ways of detecting, treating, curing, and ultimately preventing
diseases.”
“The expansion of the Burnham Institute’s world-class biomedical
research operations into Florida illustrates the strength of the state’s
international reputation as a hub for cutting edge biomedical
research and development, and we’re thrilled to welcome them to
Florida,” said Governor Bush. “Burnham and its state of the art
research facilities will have a significant impact not just on the local
economy, but within the state’s overall life sciences sector. Equally
important are the biomedical discoveries that will emanate from
Burnham, as they go about the work of devising proto-type therapies
and conducting translational research. Many factors played a role in
recruiting Burnham, and I congratulate and thank all those involved
in securing this project for the Sunshine State.”
“Expansion into Florida is a transforming event for our organiza-
tion,” said Nicolas Nierenberg, Chairman of the Board, Burnham
Institute for Medical Research. “Florida has made a huge commit-
ment to the Burnham, for which we are deeply grateful. We were
overwhelmed by the show of support for bringing Burnham to
Florida. I especially wish to thank our new partners in the Orlando
community—Mayor Buddy Dyer of the City of Orlando, The
Orlando City Council, Mayor Rich Crotty of Orange County, The
Orange County Board of County Commissioners, Metro Orlando
Economic Development Commission, and Rasesh Thakkar, CEO of
the Tavistock Group.”
Burnham plans to build a 300-person operation in Orlando.
Goals for Florida are expected to include expansion of the organi-
zation’s capabilities in chemistry, pharmacology, and functional
genomics, themes that will complement and fortify the Institute’s
current commitments to cancer, degenerative diseases, and infectious
diseases, and which will allow expansion into other areas such as
diabetes and obesity research.
“We are excited about developing robust collaborations with
Florida’s strong academic institutions,” said Reed. “One of the
attractions for our organization in expanding operations to Florida
was the tremendous support and encouragement we received from
Cancer Biology & Therapy 1057
 News

Florida’s universities. In particular, the University of Florida and the

University of Central Florida provided strong incentives, including
adjunct faculty positions for many of the scientists we recruit to
Orlando. We anticipate a synergistic effect on our existing and
future research as a result of these opportunities for collaborative
research.”
Burnham will continue to develop new research initiatives at its
current site in La Jolla, California, where it plans to grow from 750
to 900 employees over the next five years.
About Burnham Institute for Medical Research. The Burnham
Institute for Medical Research is an independent non-profit bio-
medical research institution dedicated to advancing the frontiers of
scientific knowledge in life-science and medicine, and providing the
foundation for tomorrow’s innovative therapies. The Burnham is
home to three major research centers: the Cancer Research Center,
sponsored by the National Cancer Institute, the Del E. Webb
Neuroscience & Aging Research Center, focusing on degenerative
diseases associated with aging, and the Infectious & Inflammatory
Disease Center. During its 30-year history, discoveries by Burnham
scientists have contributed to the development of new drugs for
Alzheimer’s disease, heart disease, and cancer. Today the Burnham
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employs nearly 750 persons, including more than 550 scientists,

operating with an annual budget of ~$90 million. The majority of
the Burnham’s funding is derived from competitive research grants,
but private philanthropic support is essential to advancing the medical
research mission of the organization.
For additional information about the Burnham and ways to support its research efforts, visit www.burnham.org.

1058 Cancer Biology & Therapy 2006; Vol. 5 Issue 7