Description and Location
Glioblastoma multiforme (GBM) is the most common and deadliest of
malignant primary brain tumors in adults and is one of a group of tumors
referred to as gliomas.
Classified as a Grade IV (most serious) astrocytoma, GBM develops
from the lineage of star-shaped glial cells, called astrocytes, that support
nerve cells.
GBM develops primarily in the cerebral hemispheres but can develop
in other parts of the brain, brainstem, or spinal cord.
Because of its lethalness, GBM was selected as the first brain
tumor to be sequenced as part of The Cancer Genome Atlas (TCGA
Website), a national effort to map the genomes of the many types of cancer.
In this effort, researchers discovered that GBM has four distinct genetic subtypes
that respond differently to aggressive therapies, making treatment extremely
difficult and challenging. Parallel
research Parallel research at Johns Hopkins University also contributed to
the expansion of genomic information on GBM.
Characteristics:
- Can
be composed of several different cell types .
- Can
develop directly or evolve from lower grade astrocytoma or
oligodendroglioma.
- Most
common in older individuals and more common in men than women.
- Less
common in children .
- Median
survival rate of ~15 months; 5-year survival rate of ~4% .
- The
cause is unknown, but increasingly research is pointing toward genetic
mutations .
Incidence
The incidence, or the number of new diagnoses made annually is 2
to 3 per 100,000 people in the United States and Europe. GBM accounts for 12%
to 15% of all intracranial tumors and 50% to 60% of astrocytic tumors.
Treatment
Standard treatment is surgery, followed by radiation therapy or
combined radiation therapy and chemotherapy. If inoperable, then radiation or
radiation/chemotherapy can be administered.
Treatment requires effective teamwork from neurosurgeons,
neuro-oncologists, radiation oncologists, physician assistants, social workers,
psychologists, and nurses. A supportive family environment is also helpful.
Surgery
GBM’s capacity to wildly invade and infiltrate normal surrounding
brain tissue makes complete resection impossible. However, improvements in
neuroimaging have helped to make better distinctions between tumor types and
between tumor and normal cells.
Radiation
After surgery, radiation therapy is used to kill leftover tumor
cells and try and prevent recurrence.
Chemotherapies,
an Alkylating Agent, and a Medical Device
(identified by generic names)
Temozolomide
FDA-approved in 2005 for treatment of adult patients with newly
diagnosed GBM
Bevacizumab
FDA-approved in 2009 for treatment of patients with recurrent GBM
and prior treatment
Prolifeprosan 20 with Carmustine Implant
FDA-approved in 1997 for treatment of initial occurrence GBM, an
alkylating agent that is surgically implanted as a wafer after surgical
resection and allows for drug delivery directly to the tumor site
TTF Device
FDA-approved in 2011 approved as a medical device for adult
patients with recurrent GBM after surgery and chemotherapy treatment to deliver
electric tumor-treating fields to the brain to physically break up the tumor
cell membranes
Ongoing
Research and Clinical Trials
Clinical Trials
A number of clinical trials are being conducted to search for GBM
treatments. The National Cancer Institute maintains a website that lists these
trials:
The trials involve many types of therapy, including immunotherapy,
antiangiogenic therapy, gene and viral therapy, cancer stem cell therapy, and
targeted therapy (personalized medicine).
Molecular Pathogenesis of
Malignant Glial Tumors
1.
1Departments of Clinical Pharmacy,
Neurosurgery, and Center for Cancer Research, University of Tennessee Health
Science Center, Memphis, TN
1.
Eric C.
Holland, Memorial Sloan-Kettering Cancer Center, 408 East 69th (Z1304), New
York, NY 10065, USA; e-mail: hollande@mskcc.org
Malignant glial tumors are the most aggressive and
difficult to treat neoplasms arising in the brain. More than 22,000 people in
the United States are diagnosed with a malignant glioma annually, and most will
die within the first two years from diagnosis. Traditionally, gliomas have been
categorized based solely on tumor histological features. However, expression
studies have found that molecular signatures can be used to categorize these
tumors into subclasses that more effectively predict patient outcome. The
heterogeneity between tumors as well as within individual tumors makes
understanding the molecular aspects of tumorigenesis extremely important.
Several genetically engineered mouse models (GEMMs) of glioma have been
developed that recapitulate the molecular alterations observed in the human
disease. GEMMs of glioma have allowed researchers to more closely study the
role of cancer stem cells (CSC) in gliomagenesis as well as the relevance of
signaling within the CSC microenvironment. Knowledge of the underlying
molecular signatures of malignant glial tumors coupled with the existence of a
variety of human disease-relevant GEMMs of this tumor type provide researchers
and clinicians with valuable resources for the discovery of new drug targets.
Gliomas (a primary tumor of glial cell origin) are the
most common intracranial neoplasm with astrocytomas, glioblastomas, and
oligodendrogliomas accounting for more than 80% (Central Brain Tumor Registry
of the United States [CBTRUS] 2010; Pfister, Hartmann,
and Korshunov 2009; Merchant, Pollack,
and Loeffler 2010) (Figure 1 ). More
than 22,000 people are diagnosed with a malignant glioma (also referred to as
high-grade gliomas) in the United States each year (CBTRUS 2010; Wen and Kesari 2008),
and most will die within the first two years from diagnosis despite aggressive
therapy. The World Health Organization (WHO) classifies malignant gliomas as
grades III and IV based on tumor histological and immunohistochemical features
(Louis et al.
2007). Anaplastic astrocytomas, anaplastic oligodendrogliomas, and
anaplastic oligodendroastrocytomas are classified as grade III; and
glioblastoma multiforme (GBM) and other less common variants are classified as
grade IV. GBMs, the most aggressive and deadly of these tumors, are the most
common cancer of the central nervous system (CNS) accounting for 53% of gliomas
overall (Figure 1)
(CBTRUS 2010).
By contrast, low-grade gliomas (WHO grades I and II) are relatively benign and
afford a much better prognosis as compared to their higher-grade counterparts;
however, grade II gliomas have the propensity to progress to grade IV GBMs over
time, especially in the younger population (Huse and Holland
2010).
Despite more than 40 years of research, little
improvement in mortality rates has been made for patients diagnosed with
malignant glioma owing to the intra- and inter-tumoral heterogeneity and the
propensity of the cancerous cells to infiltrate into the normal brain
parenchyma. Further complicating therapy, the blood-brain barrier prevents
chemotherapeutic agents from adequately penetrating into the tumor mass and
leads to suboptimal therapeutic response. The challenge in providing effective
therapies for the treatment of malignant gliomas is evidenced in a 5-year
survival rate (less than 5% for GBM) that has remained practically unchanged
over the past several decades. Undoubtedly, the key to developing effective
therapies is to obtain an in-depth understanding of the biological mechanisms
important to gliomagenesis.
Histological and Molecular Pathology of
Malignant Gliomas
Histological
Pathology
In 1979, the WHO formalized the first classification
system for tumors of the CNS. This system set criteria to group CNS tumors by
grade (WHO grades I through IV) (Table 1 ), with
increasing grade reflecting an increase in tumor aggressiveness and a worse
prognosis. Grade I glial tumors are benign, slow-growing, and
well-circumscribed tumors that are typically curable with resection. Grade II
glial tumors infiltrate into normal brain tissue and exhibit moderate
proliferative features. These tumors have the potential to undergo malignant
transformation (~70%) within 5 to 10 years from diagnosis (Furnari et al. 2007).
Grades III and IV tumors are classified as malignant gliomas, with grade IV
being extremely aggressive with hallmarks of vascular and uncontrolled cellular
proliferation, diffuse infiltration, and necrosis. Since the inception of this
system, three updates have been made and described in subsequent editions. Most
recently (2007), the WHO published its fourth edition that reflects changes in
tumor grade, new entities, and variants of some CNS tumors (Louis et al. 2007;
Brat et al. 2008).
This classification system has been used by clinicians, pathologists, and
scientists to collectively propel the advancement of epidemiologic and clinical
studies of brain tumors.
Molecular
Pathology
Although most gliomas are sporadic, genetics plays some
role in gliomagenesis. Patients with a family history of glioma can have a 5%
chance of developing a glial tumor (Wen and Kesari 2008;
Yanhong, Lixin,
and Huaiyin 2010). Some of the familial cases have already been linked to
rare inherited genetic abnormalities (i.e., neurofibromatosis [involving
mutations in NF1],
Turcot syndrome [abnormalities in mismatch repair genes], Li-Fraumeni syndrome
[involving mutations in TP53],
and melanoma-brain tumor [P16/CDKN2A mutations]), but
for most the etiology remains unknown (Yanhong, Lixin, and
Huaiyin 2010).
Most of the molecular alterations that have
been shown to be causal in mouse models of glioma have successfully predicted
the genetics in the human disease. Here, the focus will primarily be on the
molecular alterations that have been identified through the use of a variety of
genetically engineered glioma mouse models (Table 2 ). One
example is the functional loss of the tumor suppressors RB and P53. These
proteins function as G1-S phase cell cycle regulators and are common targets of
inactivating mutations in malignant gliomas. The RB pathway can be targeted
through the direct inactivation of RB
by gene mutation or deletion (loss of 13q) or through functional inactivation
by amplification of its negative regulators CDK4 (12q13-14) or, less commonly,
CDK6. Inactivation of p16Ink4a
prevents negative regulation of CDK4 and CDK6 and thus represents
another mechanism of RB loss of function.
Discussion
The WHO classification of tumors of the
central nervous system has been used for decades as the gold standard for
categorizing brain tumors. The most recent revisions to the WHO classification
system included changes in tumor grades and the addition of new tumor variants
and entities. However, the benefit of using molecular signatures over
histological characterization is beginning to be realized. Although tumor
histological features have historically been used as the primary consideration
for therapy selection and clinical course prediction, more recently molecular
profiling has resulted in a more effective subgrouping of these tumors and has
shed more light on the molecular pathways involved in gliomagenesis.
Genomics has proven to be extremely useful
to understanding glioma biology. It is now well understood that the molecular
signatures of adult and pediatric malignant gliomas are distinctly different,
even though histologically these tumors are indistinguishable. Molecular
subclasses have recently been identified that stratify malignant gliomas based
on expression levels of three core proteins of signaling pathways: PDGF, EGFR,
and NF1. These core proteins define subclasses that represent stages of
neurogenesis (proneural, classical, and mesenchymal, respectively).
Interestingly, these molecularly defined subclasses have proven to be better
prognostic factors than the traditional histological groups. This further
supports the importance of utilizing molecular signatures to better stratify
patients to ensure the most optimal treatment approach is employed.
In vivo models of cancer are essential for addressing
complex questions that require a disease-host interaction to more accurately
mimic the disease in humans. Several GEMMs of malignant glioma have been
developed that harbor distinct molecular defects that recapitulate the
biological environment of human brain tumors. Models of pediatric and adult
malignant gliomas provide a tool for investigating the molecular basis for the
distinct genomic differences observed between these two groups, even though
they can be histologically indistinguishable. Importantly, GEMMs have been
created that reflect the molecular signatures of the classical, proneural, and
mesenchymal molecular subclasses (Table 3). Genetic
manipulation of murine models has allowed researchers to identify genes
important to disease predisposition and drug response, as well as the discovery
of novel therapeutic targets. Additionally, these models have provided a tool
for investigating the role of CSCs in gliomagenesis.
It has been proposed that CSCs are the
cells of origin for tumorigenesis. Studies have found that CSCs are resistant
to genotoxic therapy and that treatment increases the CSC population. Mouse
models of cancer have aided researchers in understanding the biology of CSC.
The CSC perivascular niche is a microvascular-rich microenvironment that
promotes the CSC character. Identifying the diverse cell population and
signaling factors involved in maintaining the CSC phenotype within this niche
can help identify novel therapeutic targets. For example, a recent study found
that eNOS is responsible for NO production within the perivascular niche, and
elevated levels of NO activates the Notch pathway. Additionally, NO was found
to promote stem cell character and increase the stem cell population within the
perivascular niche. Indeed, the Notch pathway has already shown some promise in
brain tumor preclinical studies (Fan et al. 2006).
However, whether the Notch signaling pathway will be a fruitful target for drug
development will depend on the CSC population’s response in preclinical
studies.
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