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Gene & Protein in Disease Exploring serum inflammatory biomarkers in GBM

1. Introduction death. While several studies have been focused on serum
inflammatory biomarkers, considerable heterogeneity
Glioblastoma multiforme (GBM) is an aggressive primary persists regarding the patient populations studied, tumor
brain tumor with a median survival of 14 months under histology, biospecimen used, and timing of measurement
standard-of-care management, primarily due to tumor (e.g., pre-surgery vs. pre-chemoradiation). While it
heterogeneity, rapid proliferation, and resistance to remains unclear whether serum markers directly reflect
treatment. The current standard of care involves maximal the disease state, they have been validated in several
1,2
resection followed by concurrent chemoradiation therapy clinical contexts and are integral to standard blood
(CRT), which is comprised of radiation therapy combined work. 14-16 A limited number of inflammatory markers (e.g.,
with temozolomide, followed by adjuvant temozolomide. CRP, GFAP, IL-6, and TNF-α) can be reliably measured
3
Radiation therapy induces cell death by generating reactive in serum due to their short half-lives. 17-19 Even fewer are
oxygen species, which activate various inflammatory and directly associated with GBM, as several are influenced
immune pathways. Several studies have aimed to harness by factors such as brain volume, age, and sex. In addition,
serum data to link these pathways to clinical outcomes in molecular alterations before and after interventions,
GBM patients. Serum inflammatory biomarkers may which are not commonly measured, could identify useful
4,5
offer valuable insights into disease-related inflammation, biomarkers since only those that show significant changes
progression, and treatment response in GBM. Research are likely candidates for further development. Patient-
6,7
20
on inflammatory markers in GBM is centered on the specific and management-specific factors, including age,
quantification of neutrophils, lymphocytes, platelets, comorbidities, medications (particularly corticosteroids),
and their ratios. While these factors are associated with the timing between treatment initiation and surgery, and
radiation therapy response, they often lack sufficient individual anatomical variations, are often not accounted
specificity for disease monitoring and are subjected for in studies of inflammatory and APR markers. 20-23 In
to variability due to several clinical factors, including addition, APRs exhibit significant alterations in serum
corticosteroid use, timing of sample collection post- during the perioperative period, and corticosteroid
surgery, and comorbidities. 5,8 administration diminishes inflammation, making it
Acute phase reactants (APRs) are inflammatory difficult to interpret the significance of these markers.
24
markers significantly altered in serum during periods of These challenges have hindered the identification of
inflammation. Key APRs investigated in the context of serum biomarkers linked to clinical features in the
9
cancer, inflammation, and treatment include C-reactive absence of large-scale or multiplexed serum proteomic
protein (CRP), fibrinogen, serum amyloid A (SAA), panels. 20
9
and albumin. While measuring inflammatory APRs Therefore, there is a persistent need to identify
can be non-specific, brain-specific markers such as glial biomarkers that can elucidate the mechanisms underlying
fibrillary protein (GFAP) and brain-derived neurotrophic GBM’s complexity and treatment response, while also
factor, detectable in serum or cerebrospinal fluid, may allowing for minimally invasive biospecimen collection
offer more precise insights for GBM research. Cytokines, with robust detection capabilities. There is evidence
including interleukin (IL)-6, IL-1, tumor necrosis factor- that such markers offer opportunities for non-invasive
alpha (TNF-α), and interferon-gamma, have been shown diagnosis, monitoring, and therapy in the context of
to upregulate APRs in cancer. Previous studies have malignancy. Studying serum biomarkers, including
9,10
25
identified inflammatory serum biomarker profiles to inflammatory and acute phase markers, may enhance the
delineate prognostic subgroups of GBM patients treated standard of care by providing insights into the burden of
with standard-of-care (SOC) therapies. 11,12 These profiles disease in cancer, the impact of treatment on malignant
have been explored as potential immunotherapy targets and non-malignant tissues, and the physiological and
in medulloblastoma and for describing the effects of immune responses. The current study focuses on
13
26
radiation therapy 10,13 ; however, in most previous studies, analyzing markers in a specific clinical and histological
serum samples were collected only before treatment, diagnosis (GBM) at defined time points (before and
which does not provide sufficient information to leverage after treatment with CRT), potentially allowing for
identified markers for monitoring treatment response in a superior specificity in the measurement and behavior of
clinical setting.
these markers. The goals of this study are to (i) examine
GBM patients are treated with multiple modalities, serum inflammatory markers in GBM post-operative
including surgical tumor debulking to decrease tumor intervention and following CRT in a large-scale dataset
burden and improve neurological function, as well as to characterize their interactions and (ii) correlate serum
radiation therapy and chemotherapy to induce cell measurements with relevant pathways to determine

Volume 3 Issue 3 (2024) 2 doi: 10.36922/gpd.3580