The Silver Bullet to Brain Cancer? A Look into Novel Epigenetic Targeting of One of Glioblastoma’s Most Powerful Prognostic Indicators
Colin Chen
Glioblastoma Multiforme (GBM) is the most common primary malignant brain tumor in adults with an annual incidence of 3.19 cases per 100,000 people in the United States (Ostrom et al., 2018). This malignant tumor, characterized by its rapid growth and invasive nature, is notoriously difficult to treat effectively. Despite advancements in oncology research and therapeutic strategies, the prognosis for GBM remains grim with a median survival of approximately 12 to 15 months post-diagnosis (Stupp et al., 2005).
The current standard of care for treating glioblastoma is temozolomide (TMZ). TMZ, in stable acidic conditions found in the human body, acts as an alkylating agent that damages DNA and ideally results in apoptosis, senescence, or autophagy. However, tumor cells have a series of defense mechanisms that can perform mismatch repair and become resistant to TMZ (Liu et al., 2012). One mechanism is via the activity of O6-methylguanine-DNA-methyltransferase (MGMT), a DNA repair enzyme that repairs DNA lesions of O6 adducts created by TMZ (Yang et al., 2021). In other words, MGMT removes the alkyl group induced by TMZ to prevent DNA damage. MGMT has become a strong prognostic indicator of brain cancer: the two-year survival rate with MGMT methylation (absence of protein) is 46%, while those without methylation (presence of protein) see this rate drop to just 14% (Hegi et al., 2005). Many investigators have turned to epigenetic approaches to inhibit the activity of MGMT. Epigenetics seeks to alter gene expression rather than changing the genetic code itself.
Targeting of the epigenome can be separated into two classes: histone modifications and DNA methylation. A novel approach under DNA methylation is to methylate the promoter of MGMT to silence transcription. Methylation of the MGMT promoter occurs in approximately 50% of GBM cases and can be used as a prognostic for TMZ treatment efficacy (Sottoriva et al., 2021). Highly methylated GBMs with MGMT methylation have been observed to respond well to TMZ treatment, while GBMs with unmethylated MGMT appear to be TMZ resistant (Zhang et al. 2023).
One promising method of methylating the MGMT promoter to reduce expression is using CRISPR-based targeted hypermethylation. A recent study by University Hospital Bonn in Germany proved that targeted RNA-guided methylation of the MGMT promoter using the CRISPR/Cas9 system is a promising tool for reducing MGMT expression (Zheng et al., 2023).
Aside from direct methylation, more complex and roundabout ways to downregulate MGMT expression have also been discovered. One group at Hokkaido University found that inhibition of the STAT3 protein allowed several GBM lines to overcome resistance to TMZ and suggested that the inhibition of STAT3 reduced posttranscriptional levels of MGMT (Feng et al., 2012). Another way to downregulate MGMT is by targeting NDRG1, an MGMT stabilizing protein (Liu et al., 2013).
With infinite signaling pathways and constant development of therapeutic approaches, investigators are racing to find new ways to eliminate MGMT from the equation. The ability to potentiate all Glioblastoma cases to TMZ, regardless of MGMT methylation status, could revolutionize care and improve treatment for nearly 50% of all GBM patients. While this protein is far from the silver bullet, it is certainly a step in the right direction with the field of neuro-oncology leaping into action to learn more about it.
About the Author
Colin Chen ('26) is a junior at UNC Chapel Hill concentrating in neuroscience.
References
The current standard of care for treating glioblastoma is temozolomide (TMZ). TMZ, in stable acidic conditions found in the human body, acts as an alkylating agent that damages DNA and ideally results in apoptosis, senescence, or autophagy. However, tumor cells have a series of defense mechanisms that can perform mismatch repair and become resistant to TMZ (Liu et al., 2012). One mechanism is via the activity of O6-methylguanine-DNA-methyltransferase (MGMT), a DNA repair enzyme that repairs DNA lesions of O6 adducts created by TMZ (Yang et al., 2021). In other words, MGMT removes the alkyl group induced by TMZ to prevent DNA damage. MGMT has become a strong prognostic indicator of brain cancer: the two-year survival rate with MGMT methylation (absence of protein) is 46%, while those without methylation (presence of protein) see this rate drop to just 14% (Hegi et al., 2005). Many investigators have turned to epigenetic approaches to inhibit the activity of MGMT. Epigenetics seeks to alter gene expression rather than changing the genetic code itself.
Targeting of the epigenome can be separated into two classes: histone modifications and DNA methylation. A novel approach under DNA methylation is to methylate the promoter of MGMT to silence transcription. Methylation of the MGMT promoter occurs in approximately 50% of GBM cases and can be used as a prognostic for TMZ treatment efficacy (Sottoriva et al., 2021). Highly methylated GBMs with MGMT methylation have been observed to respond well to TMZ treatment, while GBMs with unmethylated MGMT appear to be TMZ resistant (Zhang et al. 2023).
One promising method of methylating the MGMT promoter to reduce expression is using CRISPR-based targeted hypermethylation. A recent study by University Hospital Bonn in Germany proved that targeted RNA-guided methylation of the MGMT promoter using the CRISPR/Cas9 system is a promising tool for reducing MGMT expression (Zheng et al., 2023).
Aside from direct methylation, more complex and roundabout ways to downregulate MGMT expression have also been discovered. One group at Hokkaido University found that inhibition of the STAT3 protein allowed several GBM lines to overcome resistance to TMZ and suggested that the inhibition of STAT3 reduced posttranscriptional levels of MGMT (Feng et al., 2012). Another way to downregulate MGMT is by targeting NDRG1, an MGMT stabilizing protein (Liu et al., 2013).
With infinite signaling pathways and constant development of therapeutic approaches, investigators are racing to find new ways to eliminate MGMT from the equation. The ability to potentiate all Glioblastoma cases to TMZ, regardless of MGMT methylation status, could revolutionize care and improve treatment for nearly 50% of all GBM patients. While this protein is far from the silver bullet, it is certainly a step in the right direction with the field of neuro-oncology leaping into action to learn more about it.
About the Author
Colin Chen ('26) is a junior at UNC Chapel Hill concentrating in neuroscience.
References
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