Volume 8 (will be Vol 7 on site)


What is GBM?
GBM is a type of glioma. Gliomas originate from genetic
mutations in glial cells, which provide physical and chemical
support for neurons (NORD, n.d.). According to the World
Health Organization, gliomas are divided into grades I-IV,
depending on the degree of malignancy. 

Grade I gliomas are typically benign and slow-growing, often
associated with mutations in the neurofibromin I (NF I) gene,
responsible for growth regulation (Roswell Park
Comprehensive Cancer Center, n.d.).

Grade II and grade III gliomas, characterized by rapid growth,
most often arise from mutations in the TP53 gene. This gene
is responsible for the production of a tumor suppressor
protein. Grades II and III are rare in children, but commonly
manifest in young adults. 

Grade IV gliomas are GBM, and are the most common and
malignant (Roswell Park Comprehensive Cancer Center,
n.d.). GBM is commonly seen in patients over 50 years of
age. However, there is growing evidence that GBM can also
develop in children, adolescents, and young adults. Tumors
found in younger individuals, though, are genetically unique
from those found in older adults (MDPI, n.d.).

GBM, in particular, develops from astrocytes (Fig. 1).

Glioblastoma Multiforme: Challenges and Advancements in 
Treatment
Casey Meskovich

 Abstract
Glioblastoma multiforme (GBM) is a tumor that is initiated in glial cells, usually astrocytes. GBM presents difficulties in
treatment due to the delocalization of tumor cells, inherent resistance to most cancer drugs, and the limited capacity of the
brain to repair itself. Although most cancers have demonstrated an increase in treatment efficacy associated with recent
technologies, the recovery rate of GBM has remained stagnant over the years. Recent research, focusing on the immune
response of the brain, has sparked hope for better treatments. This paper discusses why previous treatments have been
ineffective and describes the recent advancements in treatment.

Introduction
One afternoon in September of 2018, Henry Leonard’s office
hummed with the clacking of computer keys and quiet chatter
between coworkers–and, Henry’s snoring. He had been
asleep at his desk for approximately fifteen minutes before a
concerned colleague shook him awake. Taking a sip of his
coffee, Henry dismissed his lethargy as a symptom of aging;
he had always been healthy and didn’t see any other
explanation. He squinted at his computer, unsure of what
he’d been working on before falling asleep, and sighed. It
was open to an extensively chaotic weekly calendar.
Typically, Henry took pride in being well-organized, but had
recently found himself struggling to keep track of projects.

A dull ache throbbed in his temples as Henry considered the
work he had to finish that day. Preferring to avoid medication
when possible, Henry ignored the pain. As the day
progressed, his headache developed into nauseating pain.
For the first time in fifteen years, Henry swallowed an aspirin
tablet.

The day trudged on, and Henry was happy to go home. Later
that night, he called a close friend to discuss his
overtiredness, but was met with anger rather than sympathy.
Henry was shocked to learn that he had spoken to his friend
the day before, and had been aggressive and barely lucid. He
had no recollection of this conversation, and apologized
profusely.

Later that month, Henry was diagnosed with glioblastoma
multiforme, an advanced form of brain cancer. In hindsight,
these were his first symptoms–disorganization, headaches,
memory loss, and inexplicable aggression. It was a bleak
prognosis for Henry; very little is known about the causes of
the disease, and it is highly incurable. Despite being the most
common type of brain tumor, treatments for GBM have
shown minimal advancements compared to treatments for
other types of brain cancer. GBM carries an average five-
year survival rate of 7.2%, significantly lower than the overall
five-year survival rate for all types of brain cancer, which
stands at 13% (Nuffield Trust, 2023). Figure 1. An astrocyte (Ferri, 2023).

Brain Matters・Volume VII      42



external conditions (like, the presence of a new drug in the
system). The plasticity (ability of tumors to change and adapt)
of GBM, combined with the recurring nature of the tumors,
presents a difficulty in treatment.

GBM is most commonly treated with surgery, followed by
chemotherapy. Radiation therapy is also used, often after a
surgery to destroy inaccessible cancerous cells. Each of
these treatments are uniquely unsuccessful. In surgery, for
example, the delocalization of the tumor presents a problem–
GBM diffusely invades the brain, unlike tumors in other parts
of the body. As a result, it’s difficult to remove the entire
tumor with surgery (NCBI, 2020).

The presence of barriers presents a challenge for
chemotherapy. Both the blood-brain barrier (BBB) (Fig. 2)
and the blood-tumor barrier (BTB) are in effect when treating
GBM. 

The blood vessels that vascularize in the CNS are highly
selective, and function to regulate the movement of
molecules between the blood and the brain, resulting in a
membrane known as the blood-brain barrier (BBB) (NCBI,
2020). Tumors are known to compromise the BBB, resulting
in vasculature called the BTB. The BTB is characterized by a
non-uniform permeability, resulting from high heterogeneity
(NCBI, 2019), and forms during the development of
metastasis. As the tumor progresses, vasculature becomes
increasingly heterogeneous. Normal vasculature is neatly
arranged in a hierarchy of evenly spaced and well-
differentiated arteries, capillaries, venules, and veins. Vessels
supplying tumors (those that compromise the BTB) are
increasingly chaotic, often following an irregular serpentine
path (NCBI, 2010).

Selectively permeable barriers have been shown to reduce
the effectiveness of cancer therapies for GBM. Current
therapeutics have similar sizes to molecules that will not
cross the BBB, such as recombinant proteins and peptides,
antibodies, and viral vectors. This makes it difficult, if not
impossible, to find therapeutics that cross into the brain. 

Astrocytes have a multitude of functions within the brain,
ranging from clearing excess neurotransmitters, to stabilizing
and regulating the blood-brain barrier (BBB) (NCBI, 2023).
Astrocytes make up the majority of cells in the central
nervous system; this is unsurprising, considering their
versatility. 

Astrocytes also have a wide variety of locations within the
central nervous system; as a result, GBM can start anywhere
in the brain. However, it most commonly forms in the frontal
and temporal lobes, which play roles in speech, movement,
behavior, and memory. Resulting symptoms, then, coincide
with these functions; headaches, drowsiness, personality
changes, and memory loss are among the most common
(Moffitt Cancer Center, n.d.).

The intensity of these symptoms is influenced by genetic,
epigenetic, and microenvironmental factors. Uniquely, family
history is not a factor; the majority of patients have no family
history of cancerous brain tumors. There is, however, a
correlation between GBM patients and the diagnosis of close
family members–individuals with immediate relatives afflicted
with GBM are twice as likely to develop the disease. The
disease is linked to age, with a median age of 64, and is
slightly more common in men. The only controllable risk
factor for GBM is exposure to ionizing radiation therapy, as
this can contribute to genetic mutations (Moffitt Cancer
Center, n.d.). 

In most cases, the exact cause of GBM is unknown.
However, there are a few similarities between characteristics
of patients; many harbor mutations in the IDHI, EGFR, PTEN,
TP53, PI3K, and TERT genes, which are coincidentally
among the most commonly mutated genes in human beings
(NCBI, 2023). Although functions of these genes are
generally different, they all play a role in cellular pathway
signaling. In rare cases, GBM can be linked to certain genetic
syndromes, such as Turcot syndrome and neurofibrosis type
1 (NCBI, 2023).

Current Therapies and Their Success Rates
For GBM patients, options are extremely limited, as GBM
presents distinct challenges. Localization of brain tumors, the
presence of the BBB, and the limited capacity of the brain to
repair itself are among these challenges. Arguably the most,
however, is the inherent resistance to conventional
treatments (American Association of Neurological Surgeons,
n.d.).

GBM cells have stem cell properties. They’re able to self-
renew and differentiate into different cell types. This means
that tumors are often made of a number of different types of
cells, a phenomenon referred to as heterogeneity (MDPI,
n.d.). Additionally, cells are able to take on different functions
or roles within any one tumor, and change these roles as
needed. Cells in a tumor are able to interact dynamically,
forming a flexible tumor environment (MDPI, n.d.). As a
result, GBM is able to adapt quickly and effectively to 

Figure 2. Diagram of the blood brain barrier (Parashar, 2012)



aimed to specifically examine the effect of immune
checkpoint inhibitors to explain the higher response of tumors
originating outside of the brain to immunotherapy. 

It was found that T cells in tumors that did not originate in the
brain had characteristics that implied tumors were blocked
from entering the brain (Heady & Sun, 2023). Immunotherapy
led to a significant increase in T cell lymphocytes in brain
metastases, but this increase was much smaller in patients
with GBM (Heady & Sun, 2023). This data suggests that the
priming circuit is not as effective in GBM, as T cells are best
primed in draining lymph nodes outside of the brain–a
process that is not possible for tumors originating inside of
the brain. In the context of tumors, draining lymph nodes refer
to lymph nodes that receive lymphatic drainage from the area
surrounding a tumor. Tumors often stimulate the growth of
new blood vessels and lymphatic vessels to support their
growth and spread. As a result, tumor cells and antigens can
enter the lymphatic system and be transported to nearby
lymph nodes (Koukourakis & Giatromanolaki, 2022).

From these findings, researchers have suggested that
dendritic cells are a potential therapeutic strategy. Dendritic
cells are able to reach T cells in the brain, which lymph nodes
cannot do. This process would include generating dendritic
cells from patients in the lab, pulsing them with tumor-specific
proteins, and then re-injecting them back into the same
patient (Heady & Sun, 2023). By recreating the priming
process in dendritic cells, the effects of lymph node activation
can be re-created as well.

This poses exciting possibilities for the field of neuro-
oncology. Currently, the UCLA researchers are attempting
which immune cells are changing in the more responsive
tumors to help better explain the higher response rate to the
treatment. No study has comprehensively examined the
differential effect of immune checkpoint blockade treatment
on these two types of brain tumors (those that originate in the
brain, and those that metastasize to it) before. In future
studies, the researchers plan to analyze data from a larger,
more uniform group of people who were diagnosed with
melanoma that had spread to the brain (Branca, 2023).

Conclusion
Glioblastoma arises due to genetic mutations in these cells,
causing uncontrolled growth. Unlike many brain tumors,
treating glioblastoma presents specific hurdles. Challenges
include the brain tumor's location, the BBB, and the brain's
limited self-repair capacity. However, the most significant
challenge is its inherent resistance to standard treatments.

While GBM has been generally difficult to treat,
immunotherapy (which activates T-cells to target cancer
cells) has proven to be particularly unhelpful. New studies
show that this could potentially be due to a T-cell priming step
that occurs outside of the brain, whereas GBM originates in
the brain. Ongoing research into T-cell activation by dendritic
cells offers hope for patients like Henry Leonard.

Additionally, endothelial cells of vessels limit intercellular
support of large hydrophilic drugs, a category many cancer
drugs fall into (NCBI, 2023). These factors make many
therapeutics ineffective in treating GBM.

GBM also exhibits interesting resistance patterns that make it
difficult to treat. Resistance is most commonly acquired
through the mechanism of DNA enzyme repair. Some cancer
drugs (most notably temozolomide) create methyl adducts,
which inhibit normal functions, on DNA. This modification is
toxic to the cell's DNA and can trigger cell death. However,
the repair enzyme O6-methylguanine-DNA methyltransferase
(MGMT) is capable of reversing this methyl adduct,
effectively repairing the damaged DNA before it leads to cell
death (NCBI, 2020). This repair process prevents cell death
and allows cancer cells to survive the chemotherapy's
intended effects (NCBI, 2020).

Immunotherapies In Treating Cancer
While there are a few options available for GBM patients,
immunotherapy is not one of them. Immunotherapy has been
proven to be effective for various other cancers, including
some that frequently metastasize to the brain. Melanoma,
kidney cancer, and breast cancer are among these.
However, as GBM does originate in the brain,
immunotherapy has not been seen to be effective.

In tumors that don’t originate in the brain (but may potentially
metastasize to the brain), drugs called immune checkpoint
inhibitors are used. Human immune systems have several
checkpoints to regulate immune responses and prevent the
immune system from attacking healthy cells. However,
cancer cells can often take advantage of these checkpoints
to avoid being attacked by the immune system. Immune
checkpoint inhibitors are drugs that block these checkpoints,
allowing it to recognize and attack cancer cells more
effectively. These drugs have been found to elicit a significant
increase in both active and exhausted T cells—signs that the
T cells have been triggered to fight the cancer (Heady & Sun,
2023).

When the checkpoints are blocked, the immune system's
killer T-cells become more active and capable of recognizing
cancer cells as threats. T-cells are activated in lymph nodes.
During this process, antigen presenting cells are recruited to
the tumor, where they phagocytose dead or dying tumor cells
(Heady & Sun, 2023). Receptors on the dead cells activate
the antigen-presenting cells and these cells then migrate to
the nearest lymph node and prime naïve T cells moving
through there, allowing the immune system to continue to
target the tumor (Branca, 2023).

In GBM, and other tumors originating in the brain, however,
this T cell priming process isn’t effective–leading to the lack
of response to immunotherapy treatments. Researchers have
found a significant difference in the way the two types of
tumors (those that originate in the brain, and those that don’t)
respond to immunotherapy. In a study by UCLA, researchers 

Brain Matters・Volume VII      44



14. Molecular Mechanisms of Treatment Resistance in
Glioblastoma. (2020, December 31). NCBI.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794986/
15. Recurrent Glioblastoma: A Review of the Treatment
Options. (2023, August 26). NCBI.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10487236/

Moving forward, many scientists suggest a holistic approach
that combines innovative therapies, personalized medicine,
and current chemotherapies. This collective momentum in
research not only aims to improve survival rates but also
prioritizes enhancing the quality of life for individuals facing
this challenging diagnosis. 

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