Download Articles - American Scientist

A reprint from
American Scientist
the magazine of Sigma Xi, The Scientific Research Society
This reprint is provided for personal and noncommercial use. For any other use, please send a request to Permissions,
American Scientist, P.O. Box 13975, Research Triangle Park, NC, 27709, U.S.A., or by electronic mail to [email protected].
©Sigma Xi, The Scientific Research Society and other rightsholders
Feature Articles
Fighting Cancer Through the Study
of Sarcomas
Although rare, cancers of the muscle, bone or fat carry the same molecular errors
as other tumors, making them ideal subjects for the discovery of new therapies
Igor Matushansky and Robert G. Maki
A
50–year-old Finnish woman was
having mild stomach pains when
she went to see her doctor in 1996. The
physician in Helsinki found a large
abdominal mass, and things got worse
from there. Further exams discovered
tumors, 7 and 10 centimeters in diameter, on her stomach, plus many small
nodules of spreading cancer. Surgeons
removed as much of it as they could
find, but the diagnosis was grim. It
was a gastrointestinal stromal tumor,
or GIST, a cancer of the connective tissue in the gut that was inevitably fatal
if surgery failed.
Igor Matushansky is a fellow in medical oncology and a postdoctoral fellow in the laboratory of
Carlos Cordon-Cardo at Memorial Sloan-Kettering
Cancer Center in New York. He attended Columbia
University for undergraduate studies and obtained
his Ph.D. and M.D. from Yeshiva University’s
Albert Einstein College of Medicine. Following a
residency in internal medicine at the Weil-Cornell
Medical Center, his work has focused on the relation between cellular differentiation and tumor
formation and the application of this knowledge
to the management of sarcomas. Robert G. Maki
is an assistant professor at Weil Medical College
of Cornell University and an assistant member
and co-director of the Adult Sarcoma Program at
Memorial Sloan-Kettering Cancer Center. After
undergraduate studies at Northwestern University, he received his Ph.D. and M.D. from Cornell
University Medical College. He completed a fellowship and residency at the Dana Farber Cancer
Institute and Brigham and Women’s Hospital in
Boston. His publications have examined the use of
heat-shock proteins as tumor vaccines and the clinical care of sarcomas. Address for Matushansky:
Memorial Sloan-Kettering Cancer Center, 1275
York Avenue, Room C1179, New York, NY 10021.
Internet: [email protected]
414
American Scientist, Volume 93
Two years later the cancer was back,
and doctors had to operate again to remove growths on the liver and abdominal wall. Another surgery that year excised more tumors on the liver and ovary.
The woman’s doctors tried to slow the
proliferating cells with an intense barrage
of combined chemotherapeutics—seven
cycles using four different drugs over a
five-month period—without success. As
the cancer spread, it blocked the patient’s
intestine, requiring yet another operation.
When the surgeon went in to cut away
the blockage, he found and removed 45
additional tumors. The patient began
taking large daily doses of two cuttingedge, immune-system–enhancing drugs,
to little effect.
Having exhausted other options, the
woman’s oncologist, Heikki Joensuu at
the Helsinki University Central Hospital, suggested an experimental drug,
STI571, which had just begun phase I
testing for chronic myelogenous leukemia—a completely different kind of
cancer from the soft-tissue tumors his
patient carried. It was a desperate attempt to save the patient’s life, so despite the lack of any clinical supporting
data, the hospital agreed to let him try.
Two weeks later, an MRI exam
showed the woman’s tumors were
40 percent smaller. Two months later,
they had shrunk half as much again.
At eight months, they were further reduced in size; about a quarter were
no longer detectable. What’s more, the
tumor cells that remained had stopped
dividing and no longer showed the
molecular signature of cancer. It was
an incredible improvement.
Why did Joensuu think to try this
particular drug? Because he knew,
based on the work of others, the molecular basis of GIST: The abnormal
protein that caused his patient’s tumor was similar to the one that caused
the leukemia for which the drug was
approved. Furthermore, some reports
indicated that STI571 could work on
both types of proteins—at least in a
dish of cultured cells. In the end, this
success owed much to many: The
paper describing this striking case
included as coauthors doctors and
scientists from Helsinki, Turku University (also in Finland), Massachusetts Institute of Technology, Harvard,
the Oregon Health Sciences University and the pharmaceutical company
Novartis, which made the compound
(now called imatinib and sold under
the name Gleevec).
Is this drug the long-sought silver
bullet, the cure for all types of cancer?
No. But it does illustrate how discoveries in research labs can quickly pay
off in clinics. It is an early fruit from
what promises to be a great harvest of
medical advances made possible by
two decades of accelerating progress
in understanding how cells work. And
it can’t come soon enough.
Divide and Conquer
In the United States in 2005, almost
two and a half million people will be
diagnosed with some form of cancer,
and about 570,000 people are expected
to die of this disease. Indeed, cancer
passed heart disease this year as the top
killer of people under age 85. Although
© 2005 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact [email protected].
SPL/Photo Researchers, Inc.
Figure 1. From a distance, cancer looks like a single disease: Cells divide uncontrollably and haphazardly. But up close, cancer is extremely
diverse, not just because it involves different tissues, but because different genetic errors can turn a normal cell into a cancer cell. Among the
subtypes of cancer, sarcomas—a relatively rare kind of tumor—represent a considerable part of that diversity, and many of the mutations that
cause sarcomas also cause other cancers. As a result, many scientists who study the molecular basis of cancer, including the authors, use sarcoma cells as representative models for their investigations. This false-color image is a scanning electron micrograph of one type of sarcoma, a
giant cell tumor of bone (brown), infiltrating healthy bone tissue (gray).
these survival statistics would be even
grimmer without modern medicine,
the best efforts remain inadequate.
The three pillars of treatment for
cancer are surgery, radiation and chemotherapy. Of these three, chemotherapy is the least discriminating.
Whereas surgical excision and radiation therapy are site-specific, standard
chemotherapy kills dividing cells everywhere in the body. The rationale
for administering such poison is that
the cells that split frequently—usually
cancer cells—should suffer the most.
Although the strategy works well in
some instances, say for treating leukemias, other types of cancer do not grow
rapidly and are resistant to chemotherapy. Furthermore, normal cells that divide often—those in hair follicles and
the lining of the gut, for example—are
destroyed too, causing hair loss and
diarrhea. Additional medications can
alleviate some of these side effects but
do not solve the fundamental problem,
which is a lack of specificity.
www.americanscientist.org
Although new therapies based on
advances in molecular biology have
begun to enter clinical practice, the
“holy grail” of oncology—a treatment
that is both effective and completely specific to cancer cells—remains
unknown. In fact, a single cure now
seems more elusive than ever as physicians continue to learn about the many
physiological changes that distinguish
different forms of cancer from one another and from normal cells.
This heterogeneity among cancers is
reflected in a relatively rare, highly diverse class of tumors called sarcomas.
Thus, sarcomas are good (and popular) subjects for the study of therapies
that physicians can use on other types
of malignancies: More than a dozen
medical centers and hospitals around
the country specialize in sarcoma research and treatment.
The word “σαρκωµα”appears in
the writings of the physician-philosopher Galen, who lived during the latter part of the second century a.d. In
its original Greek, the term sarcoma
describes a fleshy growth. Doctors use
the word today to describe cancers
derived from connective tissues such
as bone, muscle, fat or cartilage. Each
year in the United States, clinicians
diagnose approximately 10,000 new
sarcoma cases, encompassing 50 different types of cancer, each with its
own distinctive biology.
Because relatively few people are
afflicted with each sarcoma subtype,
the disease doesn’t lend itself to studies that require many patients, such
as large-scale searches for susceptibility genes or big, randomized trials. Instead, most investigators look at
pathological mechanisms using smallscale studies that are carried out on
the cellular level. Consequently, scientists now know more about how sarcomas work than their scarcity might
suggest, and clinical trials for sarcoma
treatments are likely to reflect specific
molecular data from experiments in a
laboratory.
© 2005 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact [email protected].
2005 September–October
415
sarcomas (0.7%)
oral cavity (2.1%)
digestive system (18.5%)
respiratory system (13.5%)
skin (4.8%)
breast (15.5%)
genitals & reproductive system (23.4%)
urinary system (7.4%)
nervous & endocrine systems (3.4%)
blood (3.7%)
lymphatic system (4.7%)
other & unspecified (2.3%)
9
50
45
8
40
7
35
6
30
5
25
4
3
20
15
2
10
1
5
0
<5
5–9 10–14 15–19 20–24 25–29 30–34 35–39 40–44 45–59 60–74 75+
age
incidence per year per million
percent of cancers
10
0
Figure 2. Sarcomas are a rare subtype of cancer, accounting for less than one percent of predicted
cancer diagnoses in 2005 (top). However, these tumors make up a larger proportion of cancers
among children. Excluding Kaposi’s sarcoma (which is restricted to the elderly or patients with
suppressed immune systems), the percentage of all cancers that are soft-tissue sarcomas is highest for patients between 10 and 14 years of age (red bars). However, in absolute terms, soft-tissue
sarcomas are more likely to occur in older people (pink bars) because they get cancer more frequently than younger people. The number of diagnoses by tissue type is from the American Cancer Society’s Cancer Facts and Figures 2005 and excludes basal- and squamous-cell skin cancer.
The relative and absolute incidences of sarcomas by patient age are from Albritton 2005, based on
data from 1975 to 1999. Absolute incidence data for people 45 years and older were not included
in that report, although other studies show that the rates continue to climb with increasing age.
Our own research at Memorial
Sloan-Kettering Cancer Center in New
York strives to understand how sarcomas arise and to exploit that knowledge in the development of new treatments. Our work and the work of our
fellow physician-scientists has led to
several therapies for individual sarcomas, some of which are also proving useful in the fight against common
types of tumors, such as those found in
some lung cancers. This review highlights some of these advances.
Going After the Genes
Like other cancers, sarcomas are products of genetic mutations, which can
take many forms. One particular category of genetic errors, called chromosomal translocations, is responsible for
several sarcomas.
A chromosome is a single long
strand of DNA—thousands of times
longer than a cell is wide. When a human cell is preparing to divide, it copies each of its 23 pairs of chromosomes
so that each daughter cell can receive
a complete set. Occasionally, a strand
of DNA will break during this process. The cell usually mends these fractures correctly, or, if it cannot, trips the
self-destruct switch (leading to programmed cell death, or apoptosis). But
sometimes a cell will incorrectly join
two or more different chromosomes,
yielding a translocation. If the cell subsequently escapes its own destruction,
daughter cells can inherit too many or
too few copies of that piece of chro-
Figure 3. Normal fat cells (above, left) are characterized by their large
size, storage vacuoles and sparse nuclei (stained purple in this image). By
contrast, cells from a high-grade liposarcoma are densely packed (above,
right). The cells are shown at 400× magnification. Sarcomas tend to be
a particularly invasive form of cancer, so surgical treatments often take
surrounding healthy tissue as a precaution against leaving malignant
cells behind. In some cases the damage can be mitigated by surgical reconstruction. The image at right shows a three-dimensional projection of
computerized tomography scans from a patient with osteosarcoma who
received a bone graft and total replacement of the right hip joint. (Cell
images appear courtesy of Carlos Cordon-Cardo, Memorial Sloan-Kettering Cancer Center; CT scan is courtesy of Edward Y. Cheng, University
of Minnesota.)
416
American Scientist, Volume 93
© 2005 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact [email protected].
daughter cells
cell division
incorrect
repair
or
cell
balanced
normal
unbalanced
unbalanced
normal
normal
DNA
correct
repair
Figure 4. When a cell is preparing to divide, it must copy the DNA that makes up each chromosome so that both daughter cells receive a complete set.
The DNA strands sometimes break during this process, but most of the time the cell rejoins the correct ends with no lasting damage. However, if a
cell repairs the break incorrectly, daughter cells may inherit a so-called chromosomal translocation, in which portions of two different chromosomes
are swapped. When this happens, the outcome will be more or less harmful depending on the random sorting of chromosomes into the cellular progeny. Unbalanced translocations represent too many copies of some genes and too few copies of others; balanced translocations may cause problems
(or not) depending on the site of the break. Translocations occur in many types of tumors, but they are particularly common in sarcomas.
mosome. Furthermore, if the DNA is
snapped and incorrectly repaired in
a region that specifies a protein, that
valuable piece of the genetic code—
that gene—may be destroyed, leaving the cell with only one remaining
copy on the unbroken partner in the
chromosome pair. Another possibility
is that the improperly repaired DNA
will encode a “fusion protein,” made
from the sequences of two different
genes spliced together. Many such fusion proteins are merely ineffective,
like a bicycle with oars instead of pedals, but some can be dangerous. If the
original performed some critical function in the cell, such as regulating cell
division, the fusion protein can cause
big problems.
These breaking-and-joining events
do not happen randomly, and certain
translocations cause specific kinds of
cancer. One example is the abnormal
inheritance of an extra copy of the long
arm of chromosome 12, which causes a
version of the most common soft-tissue
www.americanscientist.org
cancer, liposarcoma—the class of sarcoma that develops from fat cells. Thanks
to recent advances in “gene profiling”
(a technique that measures gene activity), scientists have identified a cause
of one subset of this class, the so-called
dedifferentiated liposarcomas.
With two normal copies of chromosome 12 plus the extra fragment, cells
manufacture too much of the protein
encoded by one of the resident genes:
the cyclin-dependent kinase 4 gene,
a mouthful that usually goes by the
shorthand CDK4. As its name indicates,
the CDK4 protein is a kinase—an enzyme that adds phosphate groups onto
other proteins as a means of controlling
how active or inactive they are. It so
happens that this particular kinase acts
on one of the master switches of cell
division, the stoutly named retinoblastoma tumor suppressor, or RB, which
acts through a DNA-binding protein
called E2F. A glut of CDK4 causes RB
to have an excessive number of phosphate groups attached, thereby jam-
ming the cell-division switch in the on
position—a hallmark of cancer.
Once scientists understood this
chain of events, they hypothesized that
blocking CDK4 might slow the spread
of liposarcoma. One candidate drug is
flavopiridol, which inhibits several kinases, including CDK4. Our colleagues
Gary K. Schwartz and Samuel Singer at
Memorial Sloan-Kettering have shown
that this drug destroys liposarcomas in
the culture dish and in mice that carry
human liposarcomas. Several clinical
trials are now testing flavopiridol for
various cancers.
Sarcoma Antigens 101
Some tumors produce characteristic
proteins. For example, melanomas
churn out the pigment melanin and
related molecules. Thus, training the
patient’s immune system to attack
such proteins—by using a vaccine, for
example—can help the body identify
the malignant cells and get rid of the
cancer. This process of teaching the
© 2005 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact [email protected].
2005 September–October
417
three or more copies CDK4 gene (mutant)
two copies CDK4 gene (normal)
cyt
P
P
leus
m
sm plas
opla cyto
RCBDK4
nuc
E2F cell-division gene
P
P
leus
a
P
RB
P
nuc
P
CDK
4
P
P
two copies CDK4 gene (normal)
P
P
P
CDK4
P
CPDK4
P
cell-division gene
RB
P
CDK4
on
E2F
RB
sm
opla
m
cyt
las
top
c yl e u s
us
nuc
cle
nu
CDK4
P
CDK4 inactivates RB with phosphate
RB
P
P
P
P
RB
CDK4 P
P
P
P
P
P
E2F cell-division gene
CDK4
CDK4
off
off
b
flavopiridol blocks CDK4
three or more copies CDK4 gene (mutant)
iridol
P
idol
P
flavop
three or morePcopies CDK4 gene (mutant)
P
P
P
P
P
C
P
DK4
PCDK4
CDKP4
P
RB
CDK4
RCBDK4
CDK4
P
P
P
P
P
P
cell-division gene
P
B
cell-division gene
E2F
RB
R
P
P
P
CDK4
CDK4
CDK4
on
P
off
c
d
cell-division gene
P copy of the long arm of chromosome P12. One of the genes
gene
E2F cell-division
Figure 5.P Certain liposarcomas,
or cancers
of fat cells, are associated with an extra
on
in this region is CDK4, which encodes a protein that regulates one of the master switches of cell division, known as RB, by adding phosphate
off
groups (a). Normally, active and inactive forms of RB are in equilibrium, allowing some molecules to attach to the DNA-binding protein E2F,
thereby keeping the genes that control cell division turned off (b). Too much CDK4 disrupts this balance, preventing RB molecules from keepflavopiridol blocks CDK4
ing the critical genes silent (c). The drug flavopiridol attempts to restore order by inhibiting CDK4 (d).
flavopir
ol
P to create antibodies vopirid
idol
The Japanese team started by col- University of Wisconsin Children’s
immune
system
fla
three or morePcopies CDK4 gene (mutant)
flavopiridol
Hospital in Madison described their
against cancer-specific (or in the case lecting and isolating the
patient’sblocks
own CDK4
P
experiments with aidtype
of cancer
of melanin, cancer-enriched)
proteins
dendritic
cells,
a
part
of
the
immune
sysC
flavopir
DK4
ir ol
P
idol
PCDK4immunotherapy.
DKP4 whose job it is to engulf
P
C
P
flavop
called
alveolar
rhabdomyosarcoma—the
tem
invading
is called
RB
P
P
P
P
P
most
common
type
of
soft-tissue
sarSarcomas are excellent candidates
microbes, chew them up and wear
P the
P
P
P
coma
among
children.
This
sarcoma
for immunotherapy
because many pieces
on their outer membranes.
(This
P
CDK4
CDK4
RBtypically characterized
geneC
dismemberment
allows another type is
byCDK4
a translo-CDK4
have Dchromosomal
translocations
that
E2F cell-division
RB
DK4
C K4
generate fusion proteins not seen in of immune cell, the B cell, to make an- cation of chromosomes 2 and 13 that
off
any other cell of the cell-division
body. Thegene
im- tibodies that recognize each chunk, or fuses the genes PAX3 and FKHR, both P
B
P
cell-division
genetranscriptionP factors
E2F
mune Psystem can thus attack these antigen.)
of which
encode
Matsuzaki and his Rcolleagues
on
that
bind
to DNA and switch
specific molecules (and the cancer cells already knew that a translocation of (proteins
off
flavopir
P
P
P
P
P
CDK
4
P
two copies CDK4 gene (normal)
P
P
P
CDK4
P
CPDK4
sm
opla toplasm
cyt
cy
l e u su c l e u s
n
sm plasm
opla cyto
cyt
s
leus ucleu
n
nuc
nuc
E2F
P
P
sm
leus
opla
P
cyt
cyt
sm
leus
opla
nuc
American Scientist, Volume 93
nuc
E2F
418
P
nuc
P
sm
opla toplasm
cyt
cy
l e u su c l e u s
n
P
P
P
P
E2F
that contain them) without harming one of this patient’s X chromosomes
healthy tissue. Of course, the body and a chromosome 18 had fused two
does not automatically recognize the genes together so that they encoded a
mutant proteins as foreign. If it did, unique protein. In the lab, the invesblocks
CDK4
theflavopiridol
tumor never
would
have appeared tigators combined the dendritic cells
in the first place. Part of the problem withlthat protein and then returned the
flavopir
P
pirido
id
ol abnormal
is access:
The
proteins mayflavo“stimulated”
cells to the patient. The
P
not show up on the surface of the cell girl’s immune system began to recogP
at all; they may be present only within, nize the sarcoma, and the treatment
CDK4
DK4
where they are hiddenRB
from immune- Ctemporarily
suppressed the growth of
system surveillance. Fortunately, in the cancer that had spread to her lung.
some instances, fusion proteins do ap- Although such outcomes have not yet
B cell membrane,
gene been tested systematically, the strong
pear on Rthe
albeit in
E2F cell-division
quantities too small to stimulate the scientific rationale and individual sucoff
immune system. The challenge then cesses like that of Matsuzaki’s patient
is only to generate antibodies to these have sparked dozens of clinical trials
cancer-specific proteins. A few years that use a person’s own dendritic cells
ago, investigators led by Akinobu as a form of therapy for advanced canMatsuzaki at the Graduate School of cers of the kidney, prostate, breast, coMedical Sciences in Fukuoka, Japan, lon and lung.
succeeded in doing so in the treatment
of an 11-year-old girl with synovial Sarcomas and Sick Kids
sarcoma that had spread to other parts In a report published in 1997, Edmond
S. Massuda and his colleagues at the
of her body.
other genes on and off). Normally, the
PAX3 protein organizes embryonic
muscle development, and FKHR is
widespread. The fusion protein created from the melding of these genes
causes muscle cells to remain immature and hence susceptible to other
cancer-promoting events.
The investigators showed that this
fusion protein is about a hundred
times more effective at activating
PAX3-regulated genes than PAX3 itself. Massuda and his coworkers took
advantage of this property by taking
the gene for diphtheria toxin A—a potent cellular poison—and modifying it
so that it would be switched on only in
the presence of the PAX3 protein. They
then added that carefully crafted DNA
to different strains of cultured cells,
some of which carried the PAX3-FKHR
mutant. Sure enough, the additional
DNA selectively killed those cells that
manufactured the fusion protein. Fur-
© 2005 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact [email protected].
thermore, when they added the fusion
gene to otherwise normal cells, those
cells also died in the presence of the
PAX3-regulated toxin. Although the
thought of injecting toxin genes into
patients and trusting a bit of DNA
alongside to keep them from harming
the rest of the body may seem dangerous, the results from these experiments
give hope that the effects will be specific to the tumor.
Like the cancer Massuda is trying to
cure, Ewing sarcoma is one of the most
common connective-tissue tumors in
children and young adults, although
it more commonly affects bone rather
than soft tissues. It also stems from a
chromosomal rearrangement, in this
case the fusion of a gene from chromosome 22 with one from chromosome
11. The resultant protein transforms
normal bone cells into cancer cells. In
laboratory experiments, cultured bone
cells proliferate rapidly when one adds
this fusion protein and, conversely,
stop dividing when it is removed—
making the aberrant protein an ideal
therapeutic target.
One new technology for getting
rid of a particular protein in the cell is
called small interference RNA (siRNA).
In 2004, a team of clinical scientists
headed by Howard A. Chansky at the
University of Washington School of
Medicine in Seattle reported on their
successful application of this tool,
which is both powerful and specific, to
the task of suppressing the fusion protein responsible for Ewing sarcoma.
Figure 6. Many translocations that lead to cancer involve the fusion of two genes in such a
way that they encode a single protein. Scientists believe such “fusion proteins” cause several cancers, including a number of sarcomas,
by binding to DNA and disrupting normal
gene expression (top). However, because fusion proteins are unique to the cancer cells,
they also provide a means of attacking the
tumor without harming healthy tissue. In one
experimental therapy, scientists created a small
interfering RNA, or siRNA, that included a
sequence complementary to the fusion RNA.
When the two RNA strands zipped together,
the cell interpreted the double-stranded RNA
as a virus and destroyed it (middle). Another
potentially tumor-specific therapy capitalizes
on the abnormal properties of the fusion protein by adding an engineered piece of DNA
that encodes a toxin. The toxin gene only turns
on in the presence of the abnormal protein
(bottom). Thus, cancer cells, which contain
the fusion protein, create the toxin and die,
whereas normal cells lack the fusion protein,
do not turn on the toxin and are spared.
www.americanscientist.org
The approach uses many short pieces
of RNA that carry the complementary
sequence to the fusion gene’s RNA.
The interfering RNA binds to its target
to form a double-stranded molecule
that the cell perceives as a virus and
snips apart. Without its RNA template,
new copies of the fusion protein cannot
be made, and existing copies are soon
degraded. Using this strategy, Chansky and his coworkers silenced the
mutant gene in Ewing sarcoma cells in
culture, thereby preventing further cell
division. These results represent the
first use of siRNA to target the RNA
that cancer cells make, and this approach will almost certainly lead to
new therapies.
GIST Deserts
Although siRNA and similar experimental avenues for fighting cancer are
still far from routine clinical application, the use of imatinib for treating
GIST (sparked by the recovery of the
Finnish woman) has now become accepted for certain advanced cases.
How exactly does the drug work?
disease
fusion
protein
fusion
fusion
protein
protein
cytoplasm
leus
cnyut ocp l a s m
cytoplasm
nucleus
nucleus
RNA
RNA
RNA
disease
disease
fusion gene
cancer
fusion gene
fusion gene
cancer
cancer
wrong genes on
wrong genes on
wrong genes on
siRNA therapy
siRNA therapy
siRNA therapy
cytoplasm
custom
siRNA
custom
custom
siRNA
siRNA
leus
cnyut ocp l a s m
cytoplasm
nucleus
nucleus
fusion gene
fusion gene
fusion gene
genes stay off
genes stay off
genes stay off
cytopla
cancer-specific gene therapy
sm
cancer-specific gene therapy
cancer-specific gene therapy
cyto
c y t o ppllaa s m
sm
toxin gene
toxin gene
toxin gene toxin gene
toxin gene
toxin gene
toxin gene
toxin gene
toxin gene
fusion gene
fusion gene
fusion gene
fusion protein
turns on toxin
fusion protein
fusion protein
toxin gene
turns on toxin
turns on toxin
toxin gene
toxin gene
© 2005 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact [email protected].
cancer
cancer
cancer
2005 September–October
419
tinib benefits more than 80 percent of
patients. Unfortunately, this upswing
is only a respite in some cases. The
tumors vary in their genetic make-up,
which presumably explains the slow
remedy seen by some patients and the
unresponsiveness of others. The latter
group often carries tumors that have
little or no KIT protein, a variety that
can also be found among patients who
initially respond well to the drug, but
worsen as the susceptible cells die off,
leaving others to spawn new tumors
that resist imatinib.
Figure 7. Gastrointestinal stromal tumor, or GIST, is an aggressive type of sarcoma that typically resists chemotherapy and radiation, leaving surgery as the only treatment. No therapies
exist for advanced cases. However, five years ago a woman with widespread, inoperable GIST
received a speculative form of treatment based solely on her tumor’s molecular resemblance to
an unrelated form of cancer. A PET scan (which measures metabolic activity with a radioactive
tracer) taken before treatment began shows the brain, a distended kidney (a consequence of the
disease) and many abdominal tumors (left). Four weeks after starting treatment with STI571,
now called imatinib, there was no abnormal uptake of the tracer in the abdomen, indicating that
the cancer was no longer growing at an accelerated rate. (Images courtesy of Heikki Joensuu.)
GIST is usually caused by mutations
in a gene called—no kidding—v-kit
Hardy-Zuckerman 4 feline sarcoma viral
oncogene homolog. This tongue-twister,
called KIT for short, codes for a protein
also named KIT, a kinase like CDK4,
but one that adds phosphate groups
only to tyrosine—one of the 20 different types of amino acids that make up
human proteins.
Tyrosine kinases are often embedded in the outer membrane of the cell.
There, they can receive signals from
the immediate environment and transmit them to the nucleus (via a chain
of other messengers), thereby helping
to determine which genes are turned
on or off. Overactive tyrosine kinases
cause many kinds of tumors.
Although the KIT protein shows up
in other cancers, such as small-cell lung
cancer and seminoma of the testes,
only GIST contains mutations in the
gene that cause unregulated activity. In
420
American Scientist, Volume 93
a 2001 paper, David A. Tuveson, then
a postdoctoral fellow in the laboratory
of Tyler Jacks at MIT, showed that imatinib interferes with normal and mutant
KIT and inhibits the growth of cultured
GIST cells that contain the latter. These
observations helped to hasten the Food
and Drug Administration’s approval
of imatinib for the treatment of GIST
tumors that have spread so widely that
surgery is impossible—granted a scant
10 months after the publication of the
original case study. (Customarily, experimental drugs are first approved
for use in people who have exhausted
their other options.)
To grasp the striking success of imatinib, one needs to understand that prior to its use there were no good treatments for GISTs. Most of these tumors
are highly resistant to chemo- and
radio-therapy, and multiple surgeries
were the only palliative option. Now,
the combination of surgery and ima-
Beyond Sarcomas
The success of imatinib has led to investigation of a growing number of
compounds that interfere with the development of more-common (nonsarcoma) tumors in the lung, colon, breast
and prostate. Among the approved
drugs are gefitinib (Iressa) and erlotinib (Tarceva), which treat non–smallcell lung cancer (NSCLC) by inhibiting
a tyrosine kinase called the epidermalgrowth-factor receptor (EGFR). This
protein is overactive in many solid tumors and is typically associated with a
poor prognosis.
Early clinical trials of gefitinib in the
United States and Japan showed that
almost half of the patients improved
while taking the drug—remarkable
considering their tumors had resisted
standard chemotherapy. However, a
different set of studies showed that
adding gefitinib to conventional therapy did not provide an additional benefit. Nevertheless, the FDA quickly approved gefitinib for advanced NSCLC
in patients whose condition had worsened under standard therapy.
Erlotinib also works by inhibiting
the EGFR. In clinical trials, oncologists
saw modest success treating NSCLC
and bronchoalveolar carcinoma, another form of lung cancer. Evidently,
the people who responded the best to
erlotinib were those who carried mutations in their EGFR. In November of
2004, the FDA approved, after priority
review, erlotinib for the treatment of
patients with advanced non–small-cell
lung cancer who did not improve after traditional chemotherapy. Because
many of the most common cancers
contain EGFR proteins, it makes sense
to test all the available inhibitors of this
protein to find out which are best for
each combination of tumor type and
genetic constitution. Such studies are
now going on, and they should help
© 2005 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact [email protected].
improve the treatment of these types
of cancer within the next few years.
Over the past decade, scientists
have made remarkable discoveries of
the molecular mechanisms that cause
sarcomas and other cancers and are
just now seeing the payoff in the form
of treatments that specifically target
genes or proteins of those cancer cells.
However, investigators have much
more to learn about the translocationspecific sarcomas, not to mention the
large majority of cancers that do not
carry a known genetic abnormality.
It is our hope that the knowledge
obtained from the study of the better-understood sarcomas will apply
to their uncharacterized relatives and
to solid tumors as a whole, as demonstrated by recent advances in therapies
for lung cancer. We believe strongly
that the systematic analysis of these
remarkable tumors will result in an
enormous benefit to patients within
the next few years.
www.americanscientist.org
Bibliography
Albritton, K. H. 2005. Sarcomas in adolescents
and young adults. Hematology / Oncology Clinics of North America 19:527– 546.
Cheng, E. Y. 2005. Surgical management of sarcomas. Hematology / Oncology Clinics of North
America 19:451– 470.
Chansky, H. A., F. Barahmand-Pour, Q. Mei, W.
Kahn-Farooqi, A. Zielinska-Kwiatkowska, M.
Blackburn, K. Chansky, E. U. Conrad III, J. D.
Bruckner, T. K. Greenlee and L. Yang. 2004.
Targeting of EWS/FLI-1 by RNA interference
attenuates the tumor phenotype of Ewing’s
sarcoma cells in vitro. Journal of Orthopaedic
Research 22:910–917.
Dagher, R., M. Cohen, G. Williams, M. Rothmann, J. Gobburu, G. Robbie, A. Rahman,
G. Chen, A. Staten, D. Griebel and R. Pazdur.
2002. Imatinib mesylate in the treatment of
metastatic and/or unresectable malignant
gastrointestinal stromal tumors. Clinical Cancer Research 8:3034–3038.
Joensuu, H., P. J. Roberts, M. Sarlomo-Rikala, L.
C. Andersson, P. Tervahartiala, D. Tuveson, S.
L. Silberman, R. Capdeville, S. Dimitrijevic,
B. Druker and G. D. Demetri. 2001. Effect
of the Tyrosine kinase inhibitor STI571 in a
patient with a metastatic gastrointestinal stromal tumor. New England Journal of Medicine
344:1052–1056.
Massuda, E. S., E. J. Dunphy, R. A. Redman, J. J.
Schreiber, L. E. Nauta, F. G. Barr, I. H. Maxwell
and T. P. Cripe. 1997. Regulated expression of
the diphtheria toxin A chain by a tumor-specific chimeric transcription factor results in
selective toxicity for alveolar rhabdomyosarcoma cells. Proceedings of the National Academy
of the U.S.A. 94:14701–14706.
Matushansky, I., and R. G. Maki. 2005. Mechanisms of sarcomagenesis. Hematology / Oncology Clinics of North America 19:427– 449.
Matsuzaki, A., A. Suminoe, H. Hattori, T. Hoshina
and T. Hara. 2002. Immunotherapy with autologous dendritic cells and tumor-specific synthetic peptides for synovial sarcoma. Journal of
Pediatric Hematology/Oncology 24:220–223.
Tuveson, D. A., N. A. Willis, T. Jacks, J. D. Griffin,
S. Singer, C. D. Fletcher, J. A. Fletcher and G.
D. Demetri. 2001. STI571 inactivation of the
gastrointestinal stromal tumor c-KIT oncoprotein: Biological and clinical implications.
Oncogene 20:5054–5058.
© 2005 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact [email protected].
For relevant Web links, consult this
issue of American Scientist Online:
http://www.americanscientist.org/
IssueTOC/issue/761
2005 September–October
421