Sabtu, 20 April 2013

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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
2.    Eric C. Holland2
1.    1Departments of Clinical Pharmacy, Neurosurgery, and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN
2.    2Departments of Surgery, Neurosurgery, Cancer Biology and Genetics, and Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY
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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