|Genetic Analysis of Glioblastoma Brain Tumors Can Aid in Treatment
Decisions, Study Shows
Screening glioblastoma brain tumors for two gene variations can reliably predict
which tumors will respond to a specific class of drugs, a new study shows. The
findings may lead to improved treatment for this devastating disease. The study
was funded in part by the National Institute of Neurological Disorders and Stroke
(NINDS), part of the National Institutes of Health (NIH), and appears in the
November 10, 2005, issue of the New England Journal of Medicine.1
Glioblastomas are the most common malignant brain tumors in adults, and they
are notoriously difficult to treat successfully. "The survival with glioblastoma
is usually a year on average, and that hasn't improved in a while, so this is
a very serious and challenging disease," says Paul Mischel, M.D., of the David
Geffen School of Medicine and Jonsson Comprehensive Cancer Center at the University
of California, Los Angeles (UCLA), who led the study. While drugs are available
to help treat glioblastoma, they often have minimal effect, and doctors usually
have time to try only one or two treatments before the disease causes severe
impairment. Glioblastomas feature many genetic variations that affect their response
to different treatments. Researchers are trying to identify these genetic factors
and to tease apart how they affect the disease in order to determine which patients
are the most likely to benefit from specific drugs.
In the new study, Dr. Mischel and his colleagues performed genetic analysis
on tissue from recurrent malignant glioblastoma patients, 26 of whom responded
either very well or very poorly to the drugs erlotinib (Tarceva®) and gefitinib
(Iressa®). These two drugs belong to a class called EGFR (epidermal growth
factor receptor) kinase inhibitors, and both are currently approved by the by
the U.S. Food and Drug Administration (FDA) to treat advanced lung cancer that
has not responded to other treatments.
Based on results from other studies, the researchers hypothesized that variations
in several different genes might play a role in the tumor's response to EGFR
inhibitors. They looked for mutations in genes called EGFR and HER2/neu, and
they analyzed the activity of EGFR, an EGFR variant called EGFRvIII, and a gene
called PTEN. Many tumors — not just brain tumors — have mutations
or abnormal activity of one or more of these genes, which help to control cell
growth and other functions.
Glioblastomas that produced both EGFRvIII and PTEN were 51 times more likely
to shrink when treated with EGFR inhibitors than tumors without this combination
of proteins, the researchers found. Patients whose tumors expressed these proteins
and who received an EGFR inhibitor went almost 5 times longer on average before
their tumors progressed (243 days vs. 50 days) than those whose tumors did not
express both of the proteins. In contrast, EGFR and HER2/neu activity had no
effect on how tumors responded to these drugs. Similar results were found in
tissues from another group of 33 glioblastoma patients who had taken part in
a clinical trial of erlotinib at the University of California, San Francisco.
The findings suggest that both EGFRvIII and PTEN proteins are important for
tumors to be susceptible to EGFR inhibitors, Dr. Mischel says. Their data further
suggest that EGFRvIII may act to sensitize glioblastoma cells, while PTEN loss
may act as a resistance factor. The researchers tested their results in several
different cell models and repeatedly found that expression of these two proteins
made the cells sensitive to EGFR inhibitors and that PTEN loss promoted resistance
in those models.
The study shows that genetic analysis of glioblastomas can predict the tumors'
sensitivity to specific drugs. Adjusting treatment based on each tumor's genetic
activity could significantly prolong life for a subset of glioblastoma patients,
Dr. Mischel says. It also may prevent patients from undergoing unnecessary and
expensive treatments, and it could allow some people to be treated with the most
effective therapy immediately, before the tumors can grow and develop new mutations
that make them more difficult to treat.
Kinases are enzymes that play key roles in cell proliferation, metabolism, and
other functions, and they are often overactive in cancer cells. Because cancer
cells may become dependent on the persistent signals created by altered kinases
in a way in which non-cancerous cells do not, kinase inhibitors such as EGFR
inhibitors can often target cancer cells without seriously affecting the rest
of the body. Therefore they cause fewer side effects than most other cancer drugs.
The drug imatinib (Gleevec®), which is FDA-approved to treat chronic myeloid
leukemia, is one of the early success stories for this kind of treatment.
The study also reveals important information about how glioblastomas and other
tumors develop, Dr. Mischel says. Knowing that EGFRvIII and PTEN play critical
roles in tumor response to treatment could lead to new combination therapies
that target both proteins. Such therapies might also be beneficial for other
types of cancer.
Screening for these factors also might allow researchers to better determine
a treatment's effects in clinical trials, Dr. Mischel adds. Traditional clinical
trials that do not take into account each tumor's genetic makeup often fail to
show enough of an effect to warrant FDA approval for a drug because only a subset
of patients respond well to the treatment.
The researchers are now planning prospective clinical trials to determine whether
selecting treatment based on each tumor's genetic activity can lead to better
patient survival. They also plan to continue looking for other tumor susceptibility
factors, to develop new treatments that target those factors, and to try to learn
how some patients become resistant to treatment. Researchers also need to develop
their genetic screening techniques into a diagnostic test so that it can be available
to all people with glioblastoma, Dr. Mischel says.
The NINDS is a component of the NIH within the Department of Health and
Human Services and is the nation's primary supporter of biomedical research
on the brain and nervous system.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.