Above: By studying the unique genetic signatures of tumor
tissue, today's research paves the way for tomorrow's medicine.
As a fingerprint distinguishes an individual, each cancer's
genetic signature is unique.
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Brain cancerthe very words evoke fear. And
for good reason. Despite advancements in detection and treatment of other
tumor types, brain cancer continues to be one of the deadliest forms of
the disease. But thanks to technological advances and scientific breakthroughs,
the field is ripe for progress.
That's why, roughly five years ago, neuro-oncologists at
the School of Medicine joined forces to tackle this most formidable of
cancer frontiers. Today, their multidisciplinary approach incorporates
a wide range of clinical and laboratory expertise.
With access to the Alvin J. Siteman Cancer Center and cutting-edge
technologies, researchers at Washington University are pooling their resources
with several goals in mind: to understand how and why cells grow abnormally
and divide uncontrollably in order to develop better treatments; to discover
ways to predict who will become sick so that early detection is more feasible;
to appreciate differences between types of brain tumors so that more targeted
treatments can be applied to specific tumors, and to improve surgical
strategies.
Difficult and deadly challenges
According to the American Brain Tumor Association, about
13,000 Americans die each year from brain cancer. Brain tumors are the
third leading cause of cancer-related deaths in people ages 20-39 and
are even more common in adults ages 40-70. They are the second leading
cause of cancer-related deaths in children.
In the normal body, cells constantly divide, grow and die.
These processes are genetically hard-wired by a number of critical genes
that maintain the balance between cell life and death. But sometimes a
cell escapes from the programmed routine of development and deathit
grows rapidly and abnormally and forms a cancer. These abnormal cells
perpetuate and accumulate genetic mutations and then can metastasize (grow
and spread) to other areas of the body.
The brain poses a unique set of challenges. Early detection
of brain cancer is more difficultÑand arguably more importantÑthan in
most other organs. Despite improvements in brain imaging, it is not cost-efficient
to offer routine brain scans, even for individuals over the age of 55
who are at the greatest risk. Symptoms often are subtle or difficult to
diagnose. These tumors can therefore grow undetected for many years and
become resistant to therapy.
Late diagnosis is made even more frightening by the fact
that the brain is more difficult to treat than any other organ. It has
its own protective wall, the blood-brain barrier, that keeps out unwanted
elements. Unfortunately, it often also blocks chemotherapy and radiation
treatment, and poses a unique challenge for surgery.
In theory, the best way to get rid of an unwanted bundle
of cells is simply to remove it. But, once again, the brain is defiantly
difficult. It is a complex system of interwoven cells, each specialized
for different but equally vital functions and each connected to other
cells through an intricate network of communication. Even if the tumor
hasn't begun to spread, the surgical risks could outweigh the benefit.
To more effectively treat this devastating cancer, physicians
and scientists are working to develop tumor-specific therapies and to
discover ways of identifying individuals who are most likely to respond
to a given treatment.
Banking on the future
Early diagnosis of brain cancer is as challenging as it
is critical. Though there are some genetic or immune diseases that predispose
certain individuals to brain cancer, as well as evidence that points to
environmental risk factors like radiation, few cases fall into any such
category. For the most part, there is no way to predict who will develop
a brain tumor.
For several years, surgeons at the School of Medicine have
been collecting frozen samples of tumor tissue from consenting patients
and saving them in the Siteman Cancer Center Tumor Repository directed
by Mark A. Watson, MD, PhD, assistant professor of pathology. After a
biopsy is done, a sample of tissue can be stored indefinitely for experimental
analysis.
By successfully freezing cells, you can get a series
of samples and go back to look at them when the right tools are available,
says Keith M. Rich, MD, associate professor of neurological surgery, of
radiology, and of anatomy and neurobiology, who uses the samples for his
own research.
The goal of the tumor bank is to provide a resource of
biological specimens that can be used to develop genetic profiles of brain
tumors. In the same way that a fingerprint distinguishes individuals from
one another, the genetic makeup of each specific type of tumor distinguishes
it from other forms of cancer. With a large bank of tissue samples, researchers
hope to understand the distinguishing characteristics between different
tumors and to develop tailored treatment strategies for individual patients.
Taking the genetic inventory
To produce these molecular profiles for specific grades
of brain tumors, researchers employ a genetic technology called GeneChip
analysis. The technology, also referred to as DNA microarray, is provided
by the Multiplexed Gene Analysis Core at the Siteman Cancer Center, led
by Watson and William D. Shannon, PhD, assistant professor of medicine
and of the division of biostatistics. It allows researchers a panoramic
view of cancer gene expression, thousands of genes at a time.
Technologies like the GeneChip provide us a unique
perspective into the genetic domain, says Watson. We now can
step back and take inventory on a larger scale, which nicely complements
our traditional approach of examining suspect genes one at a time.
The resulting, comprehensive list of active genes is useful
both for basic science and clinical research: It helps to identify groups
of patients that might respond to different treatments already available
and also leads to frequent discoveries of new genes that can then be examined
more critically in the laboratory. Watson and his colleagues already have
begun to classify tumors using this method and are compiling genetic profiles
that may help predict clinical behavior and response to therapy.
In this pursuit to distinguish unique characteristics of
particular types of tumors, Arie Perry, MD, assistant professor of pathology,
enlists the help of another useful technique, fluorescence in situ
hybridization, or FISH. Perry uses specially designed fragments of DNA
to probe individual tumors for specific genetic regions of interest. These
DNA probes deposit a red or green fluorescent dye wherever those genetic
regions are present and these colored signals, or dots, are then visible
through a microscope.
Normal cells have two copies of each gene. Once a gene has
undergone FISH, Perry can simply examine a tissue sample and count the
dots: two red dots or two green dots signify that the gene of interest
is intact, or healthy; numerous dots suggest that the gene is amplified,
or more active than it should be; fewer than two mean that the gene has
been deleted off the chromosome. Either of the latter two scenarios might
indicate tumor growth.
In the future, I think we'll still be looking under
the microscope to make a diagnosis, says Perry. But by adding
techniques like FISH, we'll be able to get a lot more information from
our diagnosis that will be useful to the patient.
His optimism is well-founded. For years, researchers have
been puzzled by one form of brain tumor called oligodendroglioma. Though
most patients with oligodendroglioma respond well to chemotherapy, a significant
percentage do not. Using FISH, Perry and others have discovered that tumors
with specific genetic losses fewer than two red dotson two
different chromosomes, 1p and 19q, are more likely to respond to therapy
and yield a better prognosis.
Unlocking the secrets of the cancer cascade
Determining which patients will respond to treatment is
just the beginning. To really get to the bottom of brain cancer, scientists
need to understand why tumors differ from one another and then develop
a treatment alternative specifically targeted to the resistant types.
At the heart of cancer research is the desire to understand the cascade
of genetic signals and mishaps that allow a cell to become cancerous.
Unfortunately, research with human tumor specimens cannot sufficiently
answer this question.
It is impossible to determine from a diseased cell which
genetic changes were necessary and sufficient for that cell to become
cancerous. Techniques like GeneChip analysis can provide a list of changes
that occurred, but many of them might have been merely incidental.
Using cells from animals such as mice, researchers can study
pre-cancerous cells and watch as they form a tumor. They also can systematically
manipulate the genes of a cancerous cell to see, from the other side of
the equation, which manipulations might reverse or improve the process.
With a mouse, we can make single, surgically placed
genetic changes and then find out what the consequences of these alterations
are on brain tumor formation, explains David H. Gutmann, MD, PhD,
associate professor of neurology. Animal models also present the
opportunity to test potential therapies within the natural context of
a living creature. With humans, scientists are restricted to studying
the effects of new treatments on cells in a petri dish, removed from the
living environment.
Mouse models already have helped Gutmann and his colleagues
begin to understand the most commonand one of the most deadlytypes
of brain cancer, astrocytoma. Patients with a genetic disease called Neurofibromatosis
1 (NF1) often develop astrocytomas. The gene mutated in these patients,
NF1, helps regulate a molecule called RAS. In collaboration with researchers
at the University of Toronto, Gutmann's team has developed a strain of
mice, called B8, that has more RAS turned on in its astrocytes. The mice
get sick and die of classic astrocytomas at around 3 or 4 months of age.
By manipulating the activity of potential culprit genes
that may be altered during tumor development, the researchers hope to
isolate the correct sequence of necessary changes required for the cell
to become cancerous.
Such research into the underlying mechanisms of brain cancer,
combined with the latest diagnostic tools, sets the stage for a new era
in neuro-oncology therapeutics.
Using this multidisciplinary approach, we already
have made great strides toward piecing together this complex puzzle,
says Gutmann. Underneath all the laboratory and clinical work is
the hope that we will make life better for patients with brain cancer.
Minimally invasive surgical procedures may prove
safer
While researchers labor to uncover new diagnostic
and treatment strategies for brain cancer, exciting surgical options
already exist at Barnes-Jewish Hospital.
One advancement is a technique that uses the power
of magnets to maneuver around healthy and indispensable areas of
the brain. The technology, the Magnetic Surgery System (MSS), was
first tested on a human patient in 1998 at the School of Medicine
and Barnes-Jewish Hospital.
This is a fundamentally new way of manipulating
surgical tools within the brain that promises to be minimally invasive,
says Ralph G. Dacey Jr., MD, the Edith R. and Henry G. Schwartz
Professor and head of neurological surgery. It should be a
safer way of doing brain surgery because it allows us to use a curved
pathway to reach a target. Therefore we can go around sensitive
structures, such as those that control speech or vision, instead
of going through them.
Another alternative to traditional surgery is
the Gamma Knife. Despite its name, the Gamma Knife is not a knife
at all. In fact, the whole point of this tool is to avoid making
an incision. Instead, the machine surrounds a patient's head and
emits 201 beams of gamma radiation from multiple directions. Alone,
each beam is harmless. But when they converge at a particular point,
their combined strength is sufficient to treat a diseased mass of
tissue. Surgeons can therefore target a specific area of the brain
and avoid damaging cells along the way.
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