Glioblastoma Multiforme (GBM) is one of the most aggressive and deadly forms of brain cancer. Known for its rapid progression and poor prognosis, GBM presents significant challenges in treatment and management. GBM is a type of astrocytoma, originating from astrocytes, the star-shaped cells that make up the supportive tissue of the brain. It is classified as a grade IV tumor by the World Health Organization (WHO), indicating its highly malignant nature. GBM is characterized by rapid growth and a tendency to infiltrate surrounding brain tissue, making complete surgical removal nearly impossible. As a result, recurrence is common even after aggressive treatment.
Initial Presentation
Symptoms: GBM often presents with neurological symptoms that can vary depending on the tumor's location in the brain. Common symptoms include headaches, seizures, cognitive or personality changes, motor weakness, and visual disturbances.
Diagnosis: The initial diagnosis usually involves imaging studies such as magnetic resonance imaging (MRI) or computed tomography (CT) scans. A biopsy or surgical resection is performed to obtain tissue samples for histopathological examination to confirm the diagnosis and identify specific genetic mutations or markers.
The Genetic Landscape of Glioblastoma Multiforme
Several genetic alterations are commonly observed in GBM, contributing to its aggressive behavior. Key genetic mutations and alterations in GBM include:
TP53 Mutations: The TP53 gene, often referred to as the "guardian of the genome," plays a crucial role in regulating cell division and preventing tumor formation. Mutations in TP53 are found in approximately 30-35% of GBM cases, leading to uncontrolled cell proliferation.
EGFR Amplification: The Epidermal Growth Factor Receptor (EGFR) gene is amplified in nearly 40-50% of GBM cases. This amplification results in overexpression of the EGFR protein, promoting cell growth and survival, and contributing to tumor aggressiveness.
IDH1/IDH2 Mutations: Mutations in the IDH1 and IDH2 genes are present in a subset of GBM cases. These mutations are more common in secondary GBM, which arise from lower-grade gliomas. IDH mutations are associated with a better prognosis compared to IDH-wildtype GBM.
PTEN Deletions: The PTEN gene acts as a tumor suppressor by regulating cell growth and survival pathways. Deletions or mutations in PTEN are observed in about 30-40% of GBM cases.
TERT Promoter Mutations: Mutations in the promoter region of the TERT gene are found in a significant proportion of GBM cases. These mutations lead to increased telomerase activity, enabling cancer cells to maintain their telomeres and continue dividing.
Future Directions & Challenges:
Despite incremental improvements in glioblastoma treatment, the 5-year survival rate remains a low 10%. This has driven substantial research into novel approaches such as immunotherapy and precision oncology, highlighting the urgent need for better therapeutic strategies.
Biological barriers like the blood-brain barrier (BBB) and the unique tumor and immune environment present significant challenges in developing new treatments, unlike other solid tumors.
Immunotherapy has emerged as a promising area of tumor treatment. Various immune checkpoint inhibitors have demonstrated potential in multiple cancers. In both pre-clinical and clinical trials, traditional checkpoints like PD-1/PD-L1, CTLA4, and TIM3 have shown significant progress.
Due to the complexity of the tumor microenvironment and the modulation of the immune response, combination therapy is also suggested. Specifically, combining anti-PD-1 and anti-CTLA4 therapies has shown promising efficacy in recurrent GBM (rGBM).
Given the molecular heterogeneity and tumor evolution caused by single-target therapy, it is advisable to use therapies that target multiple antigens or incorporate antagonistic immunosuppressive cytokines. This is because single-target therapy often leads to recurrence and subsequent resistance to the initial treatment.
-Written by Sohni Tagore
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