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17 November 2023

Molecular Targeted Therapies in Glioblastoma Multiforme: A Systematic Overview of Global Trends and Findings

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Department of General Medicine, School of Medicine, Unversity of Zenica, Travnička 1, 72000 Zenica, Bosnia and Herzegovina
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Department of Anatomy, School of Medicine, University of Zenica, Travnička 1, 72000 Zenica, Bosnia and Herzegovina
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Department of General Medicine, Primary Health Care Center, Nikole Šubića Zrinjskog bb., 72260 Busovača, Bosnia and Herzegovina
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Department of Neurosurgery, Cantonal Hospital Zenica, Crkvice 76, 72000 Zenica, Bosnia and Herzegovina
Brain Sci.2023, 13(11), 1602;https://doi.org/10.3390/brainsci13111602
This article belongs to the Special Issue Identification of Molecular Targets and Anti-cancer Agents in Glioblastoma Multiforme: New Perspectives for Cancer Therapy
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Abstract

This systematic review assesses current molecular targeted therapies for glioblastoma multiforme (GBM), a challenging condition with limited treatment options. Using PRISMA methodology, 166 eligible studies, involving 2526 patients (61.49% male, 38.51% female, with a male-to-female ratio of 1.59/1), were analyzed. In laboratory studies, 52.52% primarily used human glioblastoma cell cultures (HCC), and 43.17% employed animal samples (mainly mice). Clinical participants ranged from 18 to 100 years, with 60.2% using combined therapies and 39.8% monotherapies. Mechanistic categories included Protein Kinase Phosphorylation (41.6%), Cell Cycle-Related Mechanisms (18.1%), Microenvironmental Targets (19.9%), Immunological Targets (4.2%), and Other Mechanisms (16.3%). Key molecular targets included Epidermal Growth Factor Receptor (EGFR) (10.8%), Mammalian Target of Rapamycin (mTOR) (7.2%), Vascular Endothelial Growth Factor (VEGF) (6.6%), and Mitogen-Activated Protein Kinase (MEK) (5.4%). This review provides a comprehensive assessment of molecular therapies for GBM, highlighting their varied efficacy in clinical and laboratory settings, ultimately impacting overall and progression-free survival in GBM management.

1. Introduction

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, representing 45.2% of malignant brain and CNS tumors [1,2,3,4]. It is classified as a grade IV diffuse astrocytic glioma by the World Health Organization (WHO) due to its invasive growth and specific histopathological and immunohistochemical features [5]. Molecular targeted therapies have emerged as a promising avenue for addressing GBM’s complexity and limited treatment options [6,7,8,9,10,11]. Frequent genetic alterations, such as p53 mutations, EGFR amplification, CDKN2a deletion, and PTEN mutations, offer potential therapeutic targets [11,12,13,14,15,16,17,18,19,20,21]. Current treatments, including surgery, radiation, and chemotherapy, yield a median survival of only 15 months for GBM patients, with frequent aggressive recurrences [12]. Patients also contend with significant psychological challenges that impact their quality of life [14].
This systematic review is driven by the critical need to consolidate and analyze key advancements in the field of molecular targeted therapies for GBM. Despite ongoing efforts, the complex nature of GBM and limited treatment options emphasize the significance of evaluating current research directions. Our primary goal is to offer crucial insights to the scientific community and healthcare professionals, contributing to the quest for more effective molecular interventions and improved outcomes for GBM patients.

2. Materials and Methods

A comprehensive systematic analysis was conducted to assess the present status of molecular targeted treatments for gliomas, aimed at providing valuable insights for scientific advancement and steering progress in this research domain. The methodology adhered to the established PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [22]. This systematic review was registered in the Open Science Framework (OSF) registry under the identifier OSF-REGISTRATIONS-UBGYC-V1.

2.1. Search Strategy

In March 2023, a literature search of English-text articles was conducted using PubMed and Web of Science. Categories of concepts related to molecular targeted therapy were explored, focusing on Glioblastoma multiforme (GBM) and excluding other specific types. The search query used was (Glioblastoma multiforme OR GBM) AND (Molecular targeted therapy OR Protein Kinase Inhibitors OR Immunotherapy OR Apoptosis) from 2000 to 2022. Details about the search methodology are provided in Appendix A.

2.2. Inclusion and Exclusion Criteria

The screening and analysis process involved multiple authors to ensure rigor and accuracy. Initially, article titles and abstracts were assessed by four authors. Subsequently, the remaining articles underwent meticulous examination by a panel of five authors. To ensure the highest level of precision, the screening process was carried out in multiple stages. Initially, two authors evaluated article titles and abstracts for relevance, with a focus on removing any duplicate entries. Following this initial phase, the remaining articles underwent comprehensive full-text scrutiny by three authors.
The inclusion criteria were rigorously adhered to, encompassing studies that met the following criteria: (1) clinical studies, (2) laboratory studies, (3) molecular targeted therapies designed specifically for GBM, (4) studies involving adult participants, and (5) studies from 2000 to 2022. Exclusion criteria were applied as follows: (1) book or book chapters, (2) conference papers, (3) narrative and systematic reviews, (4) non-English literature, (5) studies lacking data of interest (including those related to other glial tumors or studies without predefined data for extraction), and (6) studies involving pediatric populations (Figure 1).
Figure 1. PRISMA flowchart.

2.3. Data Extraction and Processing

In the systematic review, data extraction encompassed several key elements. These comprised the primary author’s name, year of publication, geographical location, study design, number of subjects (if applicable), molecular target, associated molecular pathway, as well as the approach used and principal discoveries. For the purposes of this study, categorization was performed based on the molecular mechanisms targeted by therapy. The classification is further detailed in Table 1.
Table 1. Categorization based on target therapy/pathways.

2.4. Statistical Analysis and Graphical Elements

The statistical analysis was conducted using IBM SPSS Statistics (Version 27.0., International Business Machines Corporation, Armonk, NY, USA). The analysis encompassed the processing of categorical variables, with their presentation in the form of frequencies and percentages. Graphical representations were generated for research purposes in non-commercial platforms (Google Sheets and Google Drawings). Elements utilized for depicting molecular pathways were sourced from the non-commercial database, Servier Medical Art (SMART, Manila, Philippines).

3. Results

3.1. Global Research Trends

A total of 166 studies met the eligibility criteria for the systematic review [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182]. The research trends showed that the majority of the studies were conducted in the USA, with 63 studies (38.0%) (Figure 2). China had the second-highest number of studies, with 41 (24.7%), followed by Germany with 10 (6.0%), Italy with 9 (5.4%), and Japan with 8 (4.8%). Other countries with a significant number of studies include France (5; 3.0%), Canada (6; 3.6%), and Australia (3; 1.8%). The remaining countries had one or two studies each, with India, Iran, Korea, Luxembourg, Norway, Romania, Russia, Spain, Switzerland, Taiwan, Turkey, and the United Kingdom each having one study.
Figure 2. Geographical distribution of research conduction.
The studies included in the review spanned from 2001 to 2022, with the majority of the studies conducted between 2013 and 2015, accounting for 11.4% and 12.0% of the total studies, respectively. The next highest number of studies took place in 2012, with 8.4% of the total studies. The years with the least number of studies were 2001, 2003, 2004, 2005, 2008, 2009, and 2017, each with only one study (Figure 3).
Figure 3. Temporal distribution of research of molecular target therapy of GBMs.

3.2. Study Design, Type of Target Therapy, and Molecular Mechanisms

The comprehensive systematic review incorporated a total of 27 studies (constituting 16.3% of the total) focused on clinical applications, and a substantial majority of 139 studies (making up 83.7%) were conducted within controlled laboratory environments.
Within the domain of therapeutic modalities, a significant proportion of 100 studies (60.2%) embraced a multifaceted therapeutic approach, while a slightly smaller portion of 66 studies (39.8%) concentrated on mono-therapeutic strategies. In terms of mechanistic classification, 69 studies (41.6%) were categorized under the PKP mechanism, 30 studies (18.1%) were classified under CCRM, 33 studies (19.9%) were designated under Microenvironmental Targets (MT), 7 studies (4.2%) fell under IT, and 27 studies (16.3%) were attributed to OM (Figure 4).
Figure 4. Study design, type of targeted therapy, mechanism, and combination with temozolomide. Legend: PKP—Protein Kinase Pathway Group; CCRM—Cell Cycle-Related Mechanisms; MT—Microenvironmental Mechanisms; IT—Immunomodulatory Targets; OT—Other Targets.
The most frequently encountered molecular target was found to be the Epidermal Growth Factor Receptor (EGFR), accounting for a substantial 18 instances (10.8%). Following closely were the Mammalian Target of Rapamycin (mTOR) with 12 occurrences (7.2%), Vascular Endothelial Growth Factor (VEGF) with 11 instances (6.6%), and Mitogen-Activated Protein Kinase (MEK) with 9 cases (5.4%). Phosphoinositide 3-Kinase (PI3K) and B-Raf Proto-Oncogene (BRAF) exhibited an equal number of occurrences, each accounting for 8 cases (or 4.8%), while they were attributed to 5 cases (3.0%), respectively.
VEGF, known as Vascular Endothelial Growth Factor, induces an augmentation in the vascularization of GBM. Consequently, it is categorized within the Endothelial Targets (ET) group, despite subsequently activating the Protein Kinase Phosphorylation (PKP) mechanism, akin to EGFR. With respect to Immunological Targets (IT), it encompasses molecular targets such as Extracellular Matrix Metalloproteinase Inducer (EMMPRIN), Autotaxin (ATX), and Lysophosphatidic Acid (LPA), which are associated with the ATX–LPA pathway. This pathway eventually activates Beta Catenin, emerging as a significant avenue of interest in the context of targeted therapy for GBM (Figure 5).
Figure 5. Common molecular pathways associated with target therapy of GBM. Legend: EGF—Epidermal Growth Factor; VEGF—Vascular Endothelial Growth Factor; JAK—Janus Kinase; STAT—Signal Transducer and Activator of Transcription; Wnt—Wingless-Related Integration Site; Cyclin—Regulatory proteins involved in cell cycle progression; β Catenin—Beta-Catenin; RAS—Rat Sarcoma; GTP—Guanosine Triphosphate; BRAF—B-Raf Proto-Oncogene; MEK—Mitogen-Activated Protein Kinase Kinase; ERK—Extracellular Signal-Regulated Kinase; PI3K—Phosphatidylinositol 3-Kinase; Akt—Protein Kinase B; mTOR—Mammalian Target of Rapamycin; HIFa—Hypoxia-Inducible Factor alpha; CDK—Cyclin-Dependent Kinase; MDM2—Mouse Double Minute 2 Homolog.

3.3. Findings from Clinical Studies

The total number of patients involved in 27 clinical studies is 2526, with three studies not reporting gender distribution numbers (Table 2). Among the known gender distribution data for 1244 patients, 764 (61.49%) were male and 480 (38.51%) were female, resulting in a male-to-female ratio of 1.59/1. The lowest recorded median age was 49 years, while the highest was 90 years. Upon examining the interquartile ranges, it is observed that the youngest participant in these studies was 18 years old, while the oldest was 100 years old.
Table 2. Overview of clinical studies.
In the context of GBM target therapy treatment, various therapeutic approaches and drug regimens have been explored, each yielding distinct success rates and outcomes. Notably, Imatinib exhibited no significant effect on GBM, with a median progression-free survival (mPFS) of 2.8 months (and control: 2.1 months), showing no statistical significance between the investigated and control groups [145]. In contrast, Nimotuzumab combined with temozolomide and radiation therapy resulted in similar survival times, boasting a median overall survival (mOS) of 15.9 months and a median progression-free survival (mPFS) of 10 months [165]. In the study by Desjardins et al. [54], the combination of bevacizumab with temozolomide showed activity and tolerance, with a median progression-free survival (mPFS) of 15.8 weeks. In the research conducted by Brown et al. [37], the combination of Bevacizumab with Cediranib and Gefitinib demonstrated improved progression-free survival, resulting in a progression-free survival (PFS) of 3.6 months. Additionally, Badruddoja et al. [29] found that bevacizumab, when combined with temozolomide, served as a salvage regimen for recurrent GBM, with an overall response rate from diagnosis of 51 weeks, a PFS-6 of 52%, and a median time to tumor progression of 5.5 months. Regorafenib demonstrated a survival benefit in recurrent GBM, with a survival of 24.8 months [109], while Pembrolizumab, with or without bevacizumab, proved ineffective in therapy, resulting in a progression-free survival rate of 26.0% and an overall survival of 8.8 months with bevacizumab, and a progression-free survival rate of 6.7% and an mOS of 10.3 months without bevacizumab [124]. These findings highlight the diverse landscape of therapeutic strategies and their associated outcomes in the management of GBM.

3.4. Findings from Laboratory Studies

Out of a total of 139 laboratory studies, the most common research samples were human GBM cell lines, specifically human cell cultures (HCC), accounting for 73 studies (52.52%). Subsequently, there were 60 studies (43.17%) that utilized animal samples, and 6 studies (4.32%) employed a combination of sample sources.
In animal studies, mice were predominantly used as the sample (52 studies), representing 37.41%.
Various drugs and treatment combinations demonstrated significant anti-glioma effects, including the inhibition of glioma proliferation, reduced invasion, enhanced apoptosis, and extended survival. Particular highlights include the effectiveness of O-acetyl GD2 ganglioside, Amb4269951, rSLURP-1, ILK inhibition, AAL881, and the combined mTOR1 and MEK1/2 inhibition in CDK4-dysregulated tumors. Moreover, the exploration of various molecular targets, such as EGFR, EGFRvIII, miRNAs, MET, and other signaling pathways, underscores the complex nature of glioma and the potential for targeted therapies.

3.4.1. Overview of In Vitro Laboratory Studies

The total number of in vitro studies included in the systematic review amounted to 42, constituting 25.3% of the overall study count. The GBM cell lines most frequently encountered in these studies were the U87 cell line (comprising 17 studies, or 40.5%), which featured prominently across various investigations. Following this, the U251 cell line (noted in 11 studies, or 26.2%) and the T98G cell line (present in 10 studies, or 23.8%) were also commonly employed.
Regarding potential drugs for the treatment of GBM, numerous compounds exhibited promise within the in vitro research. Particularly, Sorafenib, functioning as a multi-kinase inhibitor, showcased robust anti-glioma activity in both in vitro settings, as emphasized in the study by Siegelin et al. [132]. Furthermore, the combination of Metformin and Sorafenib was identified as an effective treatment strategy for TMZ-resistant GBM cells, as demonstrated in the investigation conducted by Aldea et al. [24]. The research by Paternot et al. [128] underscored the potential of Rapamycin and PD184352 as a combined therapeutic approach, effectively inhibiting DNA synthesis and pRb phosphorylation, especially in CDK4-dysregulated tumors (Table 3).
Table 3. Overview of in vitro studies.

3.4.2. Overview of In Vivo Laboratory Studies

The systematic review encompassed a total of 62 in vivo studies, constituting 37.4% of the overall studies included in the analysis. Among these in vivo studies, the GBM cell line U87-MG was the most prominently observed (comprising 9.67% of the total), with GSC11 and U251-MG cell lines each being mentioned in two studies. Of these in vivo studies, the majority (87%) involved animal subjects, with a predominant focus on mouse samples (74.2%). Two studies (3.2%) reported human population involvement.
Regarding potential drugs for GBM treatment, the provided studies showcased several promising therapeutic approaches. For instance, AMB4269951, as elucidated in the investigation by Takano et al. [152], demonstrated remarkable anti-tumor effects against gliomas. Rslurp-1, as evidenced by the research conducted by Saito et al. [139], exhibited notable antitumor activity, resulting in increased survival rates. AA1881, explored in the study led by Sathorn-Sumetee et al. [143], targeted BRAF, CRAF, and VEGFR, yielding inhibition of glioma growth and an extension in median survival (Table 4).
Table 4. Overview of in vivo studies.

3.4.3. Overview of Combined Laboratory Studies

Table 5 furnishes an overarching perspective on the amalgamation of in vivo and in vitro investigations pertaining to GBM, constituting a total of 32 combined studies (19.3%). One conspicuous facet of these studies is the breadth of molecular mechanisms and targets that they explore. For example, Kuan et al. [97] concentrate on receptor-based targeting strategies, with specific regard to TfR (transferrin receptor), while Guo et al. [71] delve into the realm of kinase inhibitors, particularly CDK 4/6 and PDGFRα. Moreover, various studies scrutinize molecular targets encompassing EZH2, FPR, JNK, and PI3K, thereby highlighting the intricate and multifaceted landscape of GBM.
Table 5. Overview of combined (in vivo and in vitro) studies.
These investigations also shed light on the efficacy of the therapies, with numerous studies presenting encouraging outcomes in terms of extended survival and tumor regression. For instance, Rslurp-1, Dasatinib, GNE-317, and dual mTOR1/2 inhibition yield augmented survival rates, signifying their potential utility in GBM treatment. Furthermore, the juxtaposition of therapies such as TRAIL and TMZ or PDK1 and CHK1 inhibitors reveals synergistic effects in the inhibition of tumor growth (Table 5).

4. Discussion

4.1. Global and Research Trends of GBMs

The global incidence of CNS tumors in 2019 was reported at 347,992 cases, indicating a substantial 94.35% increase from the period spanning 1990 to 2019 [183]. Notably, the incidence of brain tumors exhibited significant regional variation, with the highest rates observed in North America and the lowest in Africa. This trend was found to correlate with increasing Gross Domestic Product (GDP) per capita [184].
Examining the temporal distribution of studies in this systematic review, a notable proportion were conducted between 2013 and 2015, collectively accounting for 23.4% of the total studies. This surge in research activity post-2000s appears to be closely linked to the escalating incidence of GBM. Grech et al.’s [185] research unveiled a significant increase in GBM incidence from 2010, accompanied by a noteworthy increase in incidence risk ratio, measured at 1.16 per additional year. Projections further anticipate a 72% surge in incidence by 2050, compared to figures from 2010 [186].
Within this systematic review, clinical studies constituted 27 (16.3%) of the studies, while laboratory studies comprised the majority, accounting for 139 (83.7%). This distribution reflects the inherent challenges associated with limited patient cohorts and abbreviated survival durations. Initially perceived as predominant in developed nations, oncological diseases like GBM are now assuming the role of a significant economic and health burden in low- and middle-income countries (LMICs) [187]. The management of GBM in these settings is hindered by escalating financial constraints, a shortage of clinical trials, and restricted access to first-line therapeutic agents. The scarcity of healthcare professionals and the suboptimal quality of care further exacerbate the treatment gap for GBM in these regions [187]. Consequently, GBM imposes a substantial financial strain on the healthcare systems of impoverished nations [188,189,190,191,192,193,194,195]

4.2. Current State of Targeted Molecular Therapy in GBM Treatment

The prevailing standard of care for GBM involves the maximal surgical removal of the tumor, followed by localized chemotherapy utilizing TMZ, a second-generation imidazotetrazine known for its DNA-alkylating properties [196]. Its ability to penetrate the blood-brain barrier makes it particularly potent in treating brain tumors [197]. However, alongside its benefits, TMZ is associated with significant side effects such as myelotoxicity, ulcers, nausea, vomiting, fatigue, and harmful DNA damage. Moreover, resistance to this drug is commonplace in GBM patients [198]. To enhance the effectiveness of initial GBM treatment, it may be worthwhile to investigate a more potent combination regimen [199]. The presented findings in this review pertain to the use of therapeutic methods and chemotherapeutic agents in the treatment of GBM. These results reveal that a substantial majority of studies (60.2%) advocated for a comprehensive therapeutic approach, while a slightly smaller portion (39.8%) focused on single-strategy treatments.
In terms of mechanistic categorization, 41.6% of studies fell into the PKP mechanism, 18.1% were classified as CCRM, 19.9% were designated as Microenvironmental Targets (MT), 4.2% were categorized as IT, and 16.3% were attributed to OM. Currently, the predominant chemotherapeutic compounds employed in the management of GBM are small molecules designed to intervene with specific aberrant signaling pathways within GBM cells, including receptor tyrosine kinase activity, the PI3K/AKT/mTOR cascade, the cellular response to DNA damage, TP53 function, and inhibitors of the cell cycle [200]. The disrupted regulation of numerous signaling pathways in GBM serves as the primary catalyst for the uncontrolled proliferation of both initial and recurring tumors. This underscores the critical importance of identifying the optimal combination of targeted therapeutics for GBM treatment. It is noteworthy that most GBMs do not exhibit a singularly aberrant pathway, rendering them less amenable to targeted therapeutic approaches. This is exemplified by the lack of success observed in late-stage clinical trials of various targeted agents for GBM [200]. The most recent molecular and genomic evidence highlights the presence of diverse genetic and molecular characteristics within and between tumors in GBM [200]. This leads to variations in the expression of therapeutic targets across different tumors and regions within a single tumor. This heterogeneity in GBM may elucidate the lack of success observed in targeted treatments aimed specifically at tumor biomarkers, including drugs like cetuximab, gefitinib, erlotinib (targeting EGFR), bevacizumab (targeting VEGF), and cilengitide (targeting integrin). It is recognized as the underlying cause of resistance to these therapies.
Temozolomide, akin to dacarbazine, is an imidazotetrazine derivative. It stands out as one of the rare drugs capable of exerting its effects within the central nervous system [201]. In the treatment of GBM, TMZ’s primary mechanism of action involves methylating the O6 positions of guanine. This modification hinders DNA replication during cellular proliferation and triggers programmed cell death, or apoptosis. Following its approval by the FDA in 2005 [202], TMZ, when administered alongside surgery and radiotherapy, has solidified its position as the established and pivotal standard of care for individuals with GBM. This marked a significant milestone, as it rose to prominence as the leading initial chemotherapeutic option for GBM treatment. Findings from this study revealed that TMZ was utilized in 28% of the studies as part of a treatment regimen in conjunction with other molecular targeted therapy drugs.
In contemporary practice, TMZ is administered alongside radiotherapy as the primary treatment for GBM and as a secondary option for other malignant gliomas in cases of relapse. However, the utilization of radiotherapy and chemotherapy comes with certain limitations, and the emergence of tumor drug resistance is a common outcome. Beyond the known factors contributing to TMZ resistance, such as uncontrolled signaling pathways, DNA repair mechanisms, the persistence of cancer stem cell (CSC) subpopulations, and the activation of self-defense mechanisms [203], it is worth delving into alternative approaches that may hold promise in addressing these challenges. Mesenchymal stem cells (MSCs) are gaining traction as a therapeutic avenue in the field of cancer immunotherapy [204]. The development of chemoresistance to TMZ may arise from genetic and epigenetic alterations induced by the drugs in cancerous cells. These changes encompass the induction and selection of genes that confer a survival advantage, or the preferential selection of pre-existing cell clones with resistance. Potential alterations encompass an upsurge in drug efflux facilitated by active membrane pumps, deactivation of intracellular drugs, heightened resilience to DNA damage, and modifications in genes linked to apoptosis. These adjustments hold substantial importance in extensively heterogeneous tumors such as GBM, as treatment interventions may inadvertently promote the survival of resistant cells, potentially culminating in tumor recurrence. Nevertheless, there is evidence suggesting that combining TMZ with other molecular targeted therapies has demonstrated an improved survival rate [199].
The acquired resistance pathways in GBM involve the Src tyrosine kinase pathway, which regulates actin dynamics and the invasion of malignant glial cells [205]. Src transmits signals from the extracellular matrix and interacts with various intracellular proteins, including integrins, Eph kinase, and growth factor receptors. GBM cells exhibit higher Src tyrosine kinase activity compared to normal brain cells [206,207]. In a study by Eom et al. [208], an Src tyrosine kinase inhibitor (PP2) was examined in combination with TMZ. The findings indicated that PP2 enhanced the in vitro radiosensitivity of malignant glioma cells and inhibited invasion and migration. However, in in vivo trials, the combination led to a statistically non-significant decrease in tumor volume. On a different note, other authors [79] discovered that suppressing Src family kinase signaling could impede bevacizumab-induced GBM cell invasion, suggesting a potential strategy for overcoming GBM treatment resistance. Certain studies propose that miRNA may serve as a predictive marker for the response to TMZ treatment in GBM patients. Certain researchers propose that when combined with specific drugs, standard-dose TMZ chemotherapy may lead to an improvement in progression-free survival. As an illustration, the administration of trans sodium crocetinate (TSC), a substance known for its ability to enhance oxygen delivery, alongside standard-dose TMZ and radiotherapy proved beneficial for 59 GBM patients in a phase I/II trial conducted by Gainer et al. [209]. The outcomes revealed that 36% of patients who received TSC were still alive after two years, in contrast to 27–30% of those who underwent the standard treatment. The authors proposed that administering TSC in conjunction with the standard treatment conferred an advantage in GBM therapy [209]. According to Vengoji et al. [158] the combination of afatinib with TMZ significantly postpones the progression of GBM. In a study by Sang-Soo et al. [93], a nanocomplex targeting MALAT1 was examined, and the authors suggested that silencing MALAT1, combined with TMZ, also provided a survival benefit. Other combinations involving TMZ, such as its combination with dual mTOR1/2 inhibition, have proven to be effective therapies for resistant GBM. Similarly, the combination of Metformin and sorafenib has yielded the same effect [210,211].
In this review, the most frequently targeted molecular entity was identified as the EGFR, accounting for a substantial proportion. Following closely were the mTOR, VEGF, and MEK. PI3K and BRAF exhibited an equal number of occurrences. EGFR amplification and mutation are the most prevailing genetic alterations, occurring in more than 50% of GBM [200,212]. EGFRvIII is the most common and highly oncogenic EGFR mutant in GBM, and imaging the status of EGFRvIII could be of great value in GBM treatment [212]. VEGF induces an augmentation in the vascularization of GBM and is categorized within the ET group, despite subsequently activating the PKP mechanism, akin to EGFR. VEGFR and PDGFR are overexpressed, amplified, and/or mutated in GBM, leading to uncontrolled cell proliferation, angiogenesis, migration, survival, and differentiation [213].
Different cell lines are widely used in scientific research as valuable tools for studying various biological processes and diseases, including GBM. In this systematic review, human GBM cell lines, specifically HCC, were the most commonly utilized research samples, comprising 52.52% of the included laboratory studies. The prominent use of cell lines in GBM research highlights their importance in providing a controlled and reproducible model system for investigating the molecular mechanisms underlying GBM development and testing potential therapeutic interventions. These cell lines, such as U87, U251, and T98G, have been extensively employed in numerous investigations, demonstrating their relevance and utility in advancing our understanding of GBM biology [63,69]. In vitro studies using GBM cell lines have contributed significantly to the identification and evaluation of potential drugs for GBM treatment. Within the systematic review, 25.3% of the included studies focused on in vitro research. Notably, the U87 cell line emerged as the most frequently encountered cell line in these studies, appearing in 40.5% of the investigations. This consistent utilization of the U87 cell line underscores its importance as a representative model for studying GBM in vitro [179].

4.3. Effectiveness of Targeted Therapy in GBM Treatment

Several drugs have shown promise in the context of GBM target therapy treatment, as indicated by various outcomes, including survival time, mPFS, PFS-6, and OS data from Table 2. For instance, AZD1775 demonstrated therapeutic concentrations and good tolerability [141]. Alectinib, Palbociclib, Temsirolimus, Idasanutlin, and Vismodegib were evaluated in the NCT Neuro Master Match trial, which utilizes GBM molecular signatures for treatment [169]. However, Imatinib did not show a significant effect on GBM, with an mPFS of 2.8 months in Arm A and 2.1 months in Arm B, along with corresponding mOS values of 5.0 and 6.5 months [145]. Nimotuzumab, when combined with temozolomide and radiation therapy, exhibited promising results, with an mOS of 15.9 months and an mPFS of 10 months [165]. Bevacizumab, used in various regimens, demonstrated diverse outcomes, from activity and tolerance [29,37,54] to serving as a salvage regimen for recurrent GBM [29]. Regorafenib presented a significant survival benefit in recurrent GBM, with an mOS of 24.8 months [109]. Conversely, pembrolizumab, with or without bevacizumab, did not prove effective, resulting in a PFS-6 of 26.0% and an mOS of 8.8 months with bevacizumab, and a PFS-6 of 6.7% and an mOS of 10.3 months without bevacizumab [124]. These findings not only highlight the potential of various therapies but also emphasize the importance of assessing survival times and progression-free intervals in evaluating treatment efficacy for GBM patients.

4.4. Promising Targeted Therapies for GBM Treatment

Various targeted therapies demonstrate promising GBM treatment potential. The Anti-GD2 antibody [36] specifically targets O-acetyl GD2 ganglioside, effectively preventing glioma proliferation. AMB4269951 [152] shows antitumor effects by targeting CTL1 and significantly improving mouse survival. rSLURP-1 [139] effectively inhibits GBM growth by targeting α7 nAChR. QLT0276 in DMSO [95] inhibits integrin-linked kinase (ILK), leading to decreased glioma cell invasiveness and down-regulated proliferation and invasion. AA1881 [143] targets BRAF, CRAF, and VEGFR, significantly increasing mouse survival. EF2-siRNA [175], targeting EF2-kinase, demonstrates increased survival in rats and inhibits cell migration. Furthermore, boronated EGFR MAB + Cetuximab [176] significantly enhances survival by targeting EGFR and EGFRvIII tumors. The combination of Rapamycin + PD184352 [128] offers promise in CDK4-dysregulated tumors by providing complete inhibition of DNA synthesis and pRb phosphorylation. Tamoxifen [61] induces apoptosis and presents potential therapeutic targets for GBM. PX-866 [96] inhibits PI3K/Akt and increases survival in mice. NVP-AEW541 + Dasatinib [151] through dual IGF1R and Src inhibition increases apoptosis in glioma cells. Sorafenib [132] exhibits potent in vivo and in vitro anti-GBM activity. Plumbagin [120] effectively inhibits glioma proliferation and induces apoptosis, especially when combined with radiation. T7-modified liposomes [97] effectively penetrate the blood-brain barrier (BBB). The combination of SB203580 + Rapamycin [51] significantly inhibits tumor growth by targeting SAPK2/p38 and mTORC1. Anti-bFGF siRNA [106] holds potential for glioma treatment by inducing apoptosis. Lenvatinib + Crenolanib + Abemaciclib + Palbociclib [71], targeting PDGFRα and CDK4/6 signaling, offers a potential GBM treatment. DMC nanoparticle-mediated EZH2-siRNA [161] decreases tumor size. Targeting ID2 with anti-ID2 siRNA [180] increases sensitivity and decreases glioma apoptosis. Finally, F2 procyanidins [146] downregulate FPR and exert cytotoxic effects in mouse models.

4.5. Advantages and Disadvantages in Molecular Targeted Therapy of GBM

Precision-targeted therapies are engineered to selectively target cancer cells, potentially mitigating the adverse effects of treatment [214]. This focused approach enhances therapeutic efficacy while minimizing collateral damage to healthy tissues. Furthermore, targeted therapies can synergize with complementary treatments like chemotherapy and radiation therapy, yielding improved outcomes for patients [215]. By tailoring these therapies to the specific genetic profile of the tumor, treatment effectiveness is optimized. Additionally, precise administration through controlled targeting enhances drug delivery to the tumor site, augmenting treatment efficacy while reducing systemic toxicity [216]. Also, by accumulating comprehensive data from large-scale studies on molecular targets, researchers can harness the power of artificial intelligence to develop predictive algorithms for patient outcomes and prognosis. This emerging field holds immense promise and aligns with the ongoing advancements in neurosurgery and medical technology [217].
While targeted therapies demonstrate remarkable efficacy against specific molecular targets, the emergence of resistance in tumors over time poses a significant challenge. These therapies may not be universally effective across all subtypes of GBM due to the tumor’s intrinsic heterogeneity, making the identification of reliable targets a complex endeavor [216,218]. Moreover, the cost associated with targeted therapies, coupled with potential insurance coverage limitations, may restrict patient access to these advanced treatments, especially in lower-middle-income countries. It is essential to note that, like many treatments, targeted therapies can also induce side effects, such as skin rash, diarrhea, and fatigue, which may impact the overall quality of life for patients undergoing treatment.

4.6. Limitations of the Study

The limitations of this systematic review primarily revolve around its inclusion criteria, which restricted the analysis to studies published in English, potentially excluding relevant research in other languages. Additionally, the presence of heterogeneity among the sampled studies, such as variations in patient populations, treatment approaches, and study designs, may introduce some degree of bias and make it challenging to draw uniform conclusions.

5. Conclusions

In conclusion, this systematic review provides insights into the global and research trends of GBM and the current state of targeted molecular therapy in GBM treatment. The increasing incidence of GBM, particularly in developed regions, presents a substantial healthcare and economic burden. The distribution of clinical and laboratory studies in this review reflects the challenges associated with limited patient cohorts and abbreviated survival durations, which are particularly pronounced in low- and middle-income countries. The standard of care for GBM primarily involves maximal surgical removal of the tumor and the use of TMZ. However, resistance to TMZ is common, and exploring more potent combination regimens is crucial for enhancing GBM treatment. The findings reveal that most studies advocate for a comprehensive therapeutic approach, and the mechanistic categorization shows the importance of targeting multiple pathways. The effectiveness of targeted therapy in GBM treatment varies, and promising therapies target various molecular entities. Precision-targeted therapies offer advantages in terms of efficacy and reduced collateral damage, but resistance, tumor heterogeneity, cost, and potential side effects remain significant challenges.

Author Contributions

Conceptualization, E.B., R.P., H.B. and M.P.; methodology, E.B., R.P., L.Č. and R.S.; software, E.B.; formal analysis, L.T.L., S.K.V. and E.S.; investigation, E.B.; resources, B.J.; data curation, E.B., R.P., A.Č., F.J.-B. and A.J.; writing—original draft preparation, E.B., A.Č., R.P., H.B. and L.T.L.; writing—review and editing, E.B., H.B., R.S., E.S., A.J. and M.P.; visualization, E.B.; supervision, H.B., R.S., E.S., F.J.-B. and M.P.; project administration, E.B., and R.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Search Strategy
Search(Glioblastoma multiforme OR GBM) AND (Molecular targeted therapy)
Filterfrom 2000 to 2022
Search details((“glioblastoma”[MeSH Terms] OR “glioblastoma”[All Fields] OR (“glioblastoma”[All Fields] AND “multiforme”[All Fields]) OR “glioblastoma multiforme”[All Fields] OR “GBM”[All Fields]) AND (“molecular targeted therapy”[MeSH Terms] OR (“molecular”[All Fields] AND “targeted”[All Fields] AND “therapy”[All Fields]) OR “molecular targeted therapy”[All Fields] OR (“protein kinase inhibitors”[Pharmacological Action] OR “protein kinase inhibitors”[MeSH Terms] OR (“protein”[All Fields] AND “kinase”[All Fields] AND “inhibitors”[All Fields]) OR “protein kinase inhibitors”[All Fields]) OR (“immunotherapy”[MeSH Terms] OR “immunotherapy”[All Fields] OR “immunotherapies”[All Fields] OR “immunotherapy s”[All Fields]) OR (“apoptosis”[MeSH Terms] OR “apoptosis”[All Fields]))) AND (2000:2022[pdat])

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