Why Glioblastoma Continues to Defy Treatment Even with the Best Drugs and Radiation

Medical News: Glioblastoma, the most aggressive and lethal form of brain cancer, continues to confound scientists and devastate patients. Despite decades of research and the development of increasingly sophisticated therapies, this form of cancer resists nearly every weapon modern medicine throws at it. Now, researchers from Geisinger Commonwealth School of Medicine in Pennsylvania, United States, have undertaken a comprehensive review of why glioblastoma remains so difficult to treat. Their findings shed light on the multitude of molecular and genetic strategies glioblastoma tumors use to survive, adapt, and resist destruction.


Why Glioblastoma Continues to Defy Treatment Even with the Best Drugs and Radiation

Glioblastoma is a type of tumor that originates from astrocytes, star-shaped glial cells in the brain and spinal cord. It accounts for nearly 50 percent of all malignant brain tumors and comes with a devastating prognosis. Standard treatments involve surgery to remove the tumor, followed by six weeks of daily radiation therapy (RT) combined with an oral chemotherapy drug called temozolomide (TMZ). This is followed by monthly cycles of TMZ for up to six months. But even with this rigorous regimen, most patients survive only 12 to 15 months. This Medical News report will help readers understand why that is - and what scientists are trying to do about it.
 
DNA Repair Enzymes Help the Tumor Fix Itself
One of glioblastoma’s most dangerous traits is its ability to repair itself. When radiation or TMZ damage the tumor’s DNA, specialized enzymes like MGMT (O6-methylguanine-DNA methyltransferase) and APNG (Alkylpurine-DNA N-Glycosylase) jump into action to fix the damage. This self-repair process undermines the effectiveness of both chemotherapy and radiation.
 
Moreover, glioblastoma cells activate an internal defense system known as the DNA Damage Response (DDR), a sophisticated network of proteins that identifies and repairs damaged DNA. By exploiting DDR, glioblastoma cells survive what should be lethal treatments. The researchers emphasized that targeting DDR elements - such as through experimental drugs that inhibit key proteins like ATM - might weaken these defenses.
 
The NuRD complex, a group of proteins including CHD4, was also found to regulate the DNA repair process by controlling how accessible the DNA is to repair enzymes. Furthermore, a pathway known as NF-κB was discovered to increase MGMT levels, making glioblastoma cells even more resistant. Scientists suggest that inhibiting NF-κB could suppress MGMT and improve treatment outcomes.
 
Even The Best Chemotherapy May Not Work for Long
Temozolomide is a powerful drug, but it doesn’t work equally well in all patients. Its effectiveness depends heavily on whether the MGMT gene is active. If the gene is silenced through a process called promoter methylation, the tumor is more sensitive to the drug. Unfortunately, in many patients, the gene remains active, helping the tumor repair the damage TMZ causes.
 
The study revealed that treatments like CRISPRoff, a gene-editing technology, could potentially silence MGMT and enhance drug sensitivity. Clinical trials are also underway to combine TMZ with new agents that inhibit DNA repair enzymes like BRCA2 and Rad51, which help fix the most serious types of DNA damage.
 
The Role of Cancer Stem Cells in Recurrence
A major contributor to glioblastoma’s resistance is the presence of glioblastoma stem cells (GSCs). These cells can lie dormant for long periods, escaping the effects of chemotherapy and radiation, only to awaken later and cause tumor recurrence. They are especially protected by enzymes and pathways that enable them to evade death and rebuild the tumor.
 
In a particularly promising experiment, researchers used engineered neural stem cells to deliver targeted therapies directly to these glioblastoma stem cells. When combined with a compound called Lanatoside C, these stem cells were able to cross the blood-brain barrier and significantly reduce tumor size in mice.
 
Cancer Cells That Refuse to Die
Another key survival strategy of glioblastoma is the suppression of apoptosis - the process of programmed cell death. Tumors hijack proteins like Bcl-2 and Mcl-1 to avoid dying, even under the assault of powerful drugs. The researchers found that using drugs to block these proteins, combined with TMZ, could increase the tumor’s sensitivity and extend survival in animal models.
 
Furthermore, glioblastoma cells can resist even powerful immune therapies by activating proteins like DR5 only under certain conditions. Studies showed that DR5 activation, when combined with a molecule called TRAIL, could force the cancer cells to die, suggesting another potential treatment pathway.
 
Genetic Chaos Makes Treatment Difficult
Glioblastoma is not a uniform disease. Each tumor can contain a mix of different genetic mutations, including alterations in the EGFR, PTEN, and TP53 genes. These mutations drive aggressive growth, help the tumor avoid immune detection, and increase resistance to therapy. For example, mutations in p53 prevent the tumor from initiating cell death in response to damage, while EGFR mutations drive uncontrolled growth.
 
Mutant p53 also contributes to a dangerous inflammatory environment around the tumor, which promotes blood vessel growth and reduces immune system effectiveness. The accumulation of mutant p53 proteins further worsens drug resistance by helping repair DNA damage from treatments like TMZ.
 
Final Frontier in the Cell Cycle
The researchers also looked at how glioblastoma disrupts the normal cell cycle to promote its survival. Some glioblastoma stem cells are in a “quiescent” or sleep-like state, avoiding treatment and reactivating later. Others are highly proliferative, constantly dividing and spreading. These behaviors are controlled by proteins like Ki67 and cyclin-dependent kinases (CDKs). Targeting these molecules may hold promise for future treatments.
 
Innovative therapies are now testing drugs that specifically disrupt different phases of the cell cycle. Compounds such as flubendazole and mebendazole, originally developed for parasitic infections, have shown activity against glioblastoma in lab studies. Oncolytic viruses and interferon-based therapies are also being explored as potential tools to manipulate the cell cycle and destroy tumor cells.
 
Conclusion
Glioblastoma remains one of the most challenging cancers to treat because it uses a wide array of defense mechanisms to survive, including enhanced DNA repair, evasion of cell death, drug resistance, and genetic variability. These resistance strategies are deeply rooted in the tumor’s biology, involving key enzymes, proteins, and genetic mutations. While new treatment avenues are emerging - such as gene editing, targeted stem cell therapies, and combination regimens - there is no one-size-fits-all cure. The future of glioblastoma treatment likely lies in personalized medicine approaches that tailor therapy to each patient’s specific tumor profile. A combination of biotechnological innovations, better diagnostic tools, and multi-targeted therapies will be crucial in finally outmaneuvering this deadly disease.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.preprints.org/manuscript/202503.1011/v1
 
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