GLIOBLASTOMA MULTIFORME: GBM
Dr. Prem Pillay, Singapore

Senior Consultant Neurosurgeon with super speciality training in Neurosurgical Oncology
(Fellow at MD Anderson Cancer Center and Hospital, U of Texas, USA)

What is a GBM?

By definition, a glioblastoma multiforme (GBM) tumor is considered a grade IV tumor. This high-grade astrocytoma group is represented by the glioblastoma multiforme and variants. the gliosarcoma and giant cell glioblastoma. A malignant astrocytoma that contains areas of dead tumor cells (necrosis) is called a glioblastoma multiforme. GBM represents about 30 percent of all primary brain tumors and about-50 percent of the astrocytomas. It is more common in older adults and it affects more men than women. Nine percent of childhood brain tumors are glioblastomas.

How does it affect a person and how is it Diagnosed?

Because of its aggressive nature and fast growing ability, the first symptoms are usually due to increased pressure in the brain. Headaches, seizures, memory loss, limb weakness, speech difficulties and behavioral changes are among the most common presenting symptoms. The first procedure for most GBMs is either Craniotomy (awake or asleep) with image guided microsurgery to remove the tumor and obtain tumor for analysis including molecular genetic profiling, or a Stereotactic or Neuroendoscopic biopsy for just diagnosis. Robotic assistance and Computer guided Image guidance may be used to improve accuracy and safety.

What are the Latest Diagnostic Methods for GBMs?

New methods for diagnosing  GBMs include Molecular Genetic tests based on fluid from the Brain called CSF (Cerebrospinal Fluid) or from the Blood and this is called Liquid Biopsy. These tests may also be particularly useful for following up the results of treatments such as surgery,advanced radiation including Radiosurgery (Linac, Gamma Knife,Proton), and Targeted Molecules. They are also useful in finding actionable targets unique to the GBM and choosing appropriate molecular treatments that can cause tumor cell death or apoptosis.

What are the Latest Treatments for GBMs?

Surgery alone is usually not enough to control the GBM because of its aggressive nature whereby its cells quickly infiltrate throughout the brain. Advances in Surgery include Immunoflorescense microscopy to visualize malignant brain tumor cell clusters and lasers/Ultrasonics for maximizing tumor resection (complete and supra-maximal). Thus, radiation therapy including advanced Radiosurgery (LINAC-Photons, Gamma Knife, Proton/Carbon Therapy)  almost always follows surgery or biopsy to attempt to control the spread of the cells. Targeted Molecular Therapies are also used to treat this tumor.

Latest Treatments :

Targeted Therapies for GBM and Gliomas

Targeted therapies for glioblastoma multiforme (GBM) and gliomas are based on molecular genetic analysis of the tumors, aiming to inhibit specific pathways and proteins that are critical for tumor growth and survival. These therapies are designed to minimize off-target toxicities in normal cells, contrasting with conventional cytotoxic chemotherapy.

Key Molecular Targets

  1. Epidermal Growth Factor Receptor (EGFR):
    • EGFR Amplification: EGFR is amplified in many GBMs, particularly in the classical subtype. Targeting EGFR with inhibitors has shown potential and improved survival but the effectiveness can be limited due to tumor heterogeneity and resistance mechanisms.
  1. Vascular Endothelial Growth Factor (VEGF):
    • VEGF Inhibitors: is a notable example of a clinically approved targeted therapy for progressive recurrent GBM. It works by inhibiting angiogenesis, which is crucial for tumor growth.
  1. p53 Pathway:
    • p53 Restoration: Efforts have been made to restore the function of p53, a tumor suppressor, by inhibiting negative regulatory proteins such as MDM2 and MDM4. This approach aims to neutralize defective MDM2 and MDM4 produced by amplification in GBM patients.
  1. Neurotrophic Tyrosine Receptor Kinases (NTRK):
    • NTRK Fusion: NTRK gene fusions, though rare in glioblastoma, have shown significant response to targeted therapies which have been effective in treating infantile GBM and other NTRK fusion-positive tumors.
  1. IDH Mutations:
    • IDH Inhibitors: For IDH1/2-mutant gliomas, targeted therapies  have been  to stop the growth of tumor cells by blocking specific enzymes needed for cell growth.
  1. FGFR-TACC Fusions:
    • FGFR Inhibitors: have demonstrated antitumor activity in recurrent GBM with FGFR-TACC gene fusions. These drugs are being studied in ongoing clinical trials.

Challenges and Future Directions

  • Tumor Heterogeneity: The heterogeneity of glioblastoma poses a significant challenge in achieving consistent success with targeted therapeutic strategies. Tumors often develop resistance mechanisms, limiting the effectiveness of targeted therapies.
  • Personalized Medicine: The use of molecular profiling to determine individualized treatment plans is becoming increasingly important. This approach involves analyzing the tumor’s genetic makeup to identify specific targets for therapy.
  • Combination Therapies: Combining targeted therapies with other treatments, such as chemotherapy and immunotherapy, may offer improved clinical outcomes. This approach aims to overcome the limitations of single-agent therapies.
  • Tumor Treatment Fields (TTF): This is new and non-invasive technique where an external device is used to create alternating electric Fields that pulse through the scalp and disrupt the GBM tumor cells so they stop dividing and/or cause cell death..

In summary, targeted therapies for GBM and gliomas are evolving rapidly, with ongoing research focusing on identifying and inhibiting specific molecular pathways that drive tumor growth and survival. Despite challenges, these therapies hold promise for improving treatment outcomes for patients with these aggressive brain cancers. Dr Prem Pillay remains optimistic that the intense research into these tumors  will allow improved survival outcomes.

References

1. Protocols of the Singapore Brain Spine Nerves Center

2. Tumor Treating Fields Therapy for Glioblastoma. O Rominyi et al. Brit J of Cancer 124-697, 2021

3. Proton Therapy for Glioblastoma
MD Anderson Cancer Center
https://www.mdanderson.org/publications/cancer-newsline/proton-therapy-for-glioblastoma.h35-1589046.html