A Systematic Review of Therapies for the Treatment of Glioblastoma

We know that glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with a poor prognosis and limited effectiveness of standard treatments (surgery, chemotherapy, radiotherapy). New therapies aim to reduce the recurrence rate and improve outcomes, focusing on GBM stem cells, the blood-brain barrier and advanced drug delivery techniques. This article presents a systematic review of the literature from the following work: Approaches in Adult Glioblastoma Treatment published in late August 2024. The article contains technical terms and is not easy to read, however, you can use the information to discuss with the team of specialists following your case by proposing insights into the innovative therapies mentioned in this article.

Glioblastoma is characterized by complex genetic changes that affect cell proliferation, survival, invasion of healthy tissue and resistance to apoptosis (natural process that leads to programmed cell death). New therapeutic strategies aim to improve prognosis, including immunotherapy, targeting of glioblastoma stem cells (GSCs), blood-brain barrier (BBB) ​​research, and advanced drug delivery systems. Tumor treating fields (TTFs), used in conjunction with radiation and chemotherapy, have shown an increase in median survival from 16 to 20.9 months. Other innovative therapies, such as therapeutic vaccines and the use of stem cells, are being tested. Despite progress, glioblastoma remains difficult to treat, with a median survival of approximately 15 months and only 5.5% of patients surviving beyond five years. Advances in the molecular understanding of glioblastoma have allowed a more precise characterization of the tumor microenvironment, highlighting intratumoral and intertumoral heterogeneity. This diversity reduces the effectiveness of conventional therapies, especially in recurrent tumors, which often present with different molecular profiles compared to the initial diagnosis. In addition, glioblastoma is protected by the BBB, which limits the efficacy of drugs. The use of oncolytic viruses and re-irradiation are other promising approaches for recurrent tumors, although efficacy and toxicity remain to be clearly assessed. Emerging therapies aim to overcome current limitations, but require further clinical trials to validate their efficacy and improve outcomes for patients with GBM. The systematic review I present followed the PRISMA guidelines for organization and presentation of results. An electronic search of several databases, including PubMed, Embase, Scopus, Web of Science, and Cochrane, was conducted for the period from January 2019 to May 2024. Inclusion criteria included studies of emerging therapies for the treatment of glioblastoma in adults, published in English, with experimental and observational studies. Non-human studies, pediatric studies, non-peer-reviewed articles, systematic reviews, and conference abstracts were excluded. 755 articles were identified, which were then reduced to 421 after removing duplicates. After screening titles and abstracts, 72 articles remained, of which only 47 had full texts available. Ultimately, 24 articles were included in the review. Article assessment was conducted by two independent reviewers, with a third reviewer included in case of disagreement. Article quality was assessed using the Joanna Briggs Institute (JBI) assessment tools. Articles were classified as low, moderate, or high risk of bias. Most studies scored highly, with a few articles showing significant limitations. In short, the review was very rigorous to truly understand what is new. Below we describe a brief description of the most innovative therapies emerging.

N-cadherin antagonist
A new approach to treating GBM uses the N-cadherin antagonist, Compound 15, which has shown significant efficacy in preclinical models. N-cadherin is a protein involved in cell-cell adhesion, which is particularly important for the growth and spread of tumors. In tumors such as GBM, these proteins help tumor cells stay connected to each other, facilitating the formation of tumor masses (spheroids) and their ability to invade surrounding tissue. Compound 15 was developed as an N-cadherin antagonist, meaning it blocks this protein, interrupting the adhesion between tumor cells. This physically breaks up the tumor cells, making them more vulnerable to treatment and preventing the formation of new masses. At a concentration of 5 mM, the viability of treated cells dropped from 82.6% to 16.8% over 30 days. In summary, N-cadherin antagonism prevents tumor cells from sticking together, making them easier to destroy and preventing the formation of new tumors.

Glioblastoma Stem Cell (GSC) Targeted Therapies
Glioblastoma stem cells (GSCs) are known to be responsible for tumor recurrence and resistance to standard treatments. These cells show resistance to several drugs, including cisplatin and etoposide. Tamoxifen has shown significant cytotoxic activity against these cells, suggesting that GSC-targeted therapies may offer a new avenue to overcome resistance and improve long-term survival.

Metabolic Pathway Inhibitors
Metabolic pathway inhibitors aim to target specific alterations in GBM metabolism. AG-881, an inhibitor of IDH1/2 mutations, has reached advanced stages of clinical trials, demonstrating a reduction in 2-HG levels and suppression of tumor growth. Other inhibitors, such as CB-839, which target glutaminase, are being studied in combination with radiotherapy and chemotherapy to improve the efficacy of treatment.

Nanoparticle-based therapies
Nanoparticles offer an innovative approach to the treatment of GBM, improving the targeted delivery of drugs. Silica-coated gold nanoparticles (AuNP-SHINs) have been shown to be selective in targeting tumor cells, but have encountered difficulties in penetrating the nucleus of tumors due to their size. Optimizing the size of nanoparticles and developing strategies to improve their penetration could increase the therapeutic efficacy of this approach.

Combination of metabolic inhibitors and traditional therapies
The combination of metabolic inhibitors such as rapamycin and doxycycline or etomoxir with traditional therapies has shown significant potential in reducing the proliferation of GBM tumor cells. The combinations target multiple metabolic pathways simultaneously, increasing therapeutic efficacy and reducing tumor resistance. These approaches could represent a breakthrough in the fight against treatment-resistant GBM.

PI3K/mTOR pathway inhibitors
PI3K/mTOR pathway inhibitors, such as eCF324, have shown promising antiproliferative results in preclinical models of GBM. eCF324 demonstrated strong efficacy, especially when combined with GDC0941, a pan-PI3K inhibitor. This combination produced a significant synergistic effect, significantly reducing tumor cell growth. This type of therapy offers new possibilities to target specific signaling pathways involved in GBM growth.

Novel Tyrosine Kinase Inhibitor
K905-0266 is a novel tyrosine kinase inhibitor with the potential to target both GBM cells and cancer stem cells (CSCs). The compound reduced cell viability and increased levels of apoptosis, demonstrating efficacy in reducing tumor sphere formation, indicative of its action against therapy-resistant cells. This inhibitor may therefore represent a promising option to target tumor cells and their stem cell counterparts.

Adenovirus Ad5-Ki67/IL-15
Ad5-Ki67/IL-15 is an oncolytic adenovirus that uses the Ki67 promoter to selectively infect GBM tumor cells. This virus significantly increases the expression of interleukin-15 (IL-15), a protein that stimulates the immune response against the tumor. In preclinical models, it reduced GBM cell viability and reduced VEGF secretion, thereby blocking angiogenesis (the process of forming new blood vessels). The efficacy of the virus was monitored through techniques such as ELISA to measure IL-15 and VEGF, confirming its potential as a targeted treatment.

Flavonoid hybrids: 2-aminothiazole
A new series of hybrid flavonoid compounds such as 2-aminothiazole have shown potential in the treatment of GBM, due to their ability to bind to the Tau protein, which is overexpressed in many types of brain tumors. These compounds inhibit Tau fibrillation, reduce cell migration and induce mitochondrial fission. This approach could represent a new strategy to block the growth and spread of GBM cells.

CAR-T Cells Targeting CD70
CAR-T cell therapies targeting CD70 have shown significant potential in the treatment of GBM, especially in recurrent cases. CD70 is overexpressed in recurrent GBM and its reduction by knockdown has been shown to decrease tumorigenicity in vitro and in vivo. CAR-T cells targeting CD70 have improved survival rates in animal models, highlighting their ability to induce a robust immune response against the tumor.

Radiotherapy and TMZ
Standard treatment for GBM includes surgical resection followed by radiotherapy and temozolomide (TMZ). However, these therapies show limited efficacy against recurrence. Transcriptomic profiling studies on recurrent tumor samples have identified genes involved in angiogenic and immune processes as potential targets for immunotherapy, paving the way for new therapeutic combinations.

Ticagrelor: P2Y12 receptor inhibitor
Ticagrelor, a P2Y12 receptor antagonist, has been shown to reduce cell viability and proliferation in GBM cell lines. The treatment also increased autophagy, reducing the migratory activity of tumor cells. This promising approach could be integrated into therapeutic strategies to reduce the invasive capacity of GBM.

Anti-OAcGD2 antibody and TMZ
The combination of anti-OAcGD2 antibodies and TMZ improved therapeutic efficacy in targeting GBM tumor stem cells, which are particularly resistant to chemotherapy. This combination showed a significant reduction in tumor volume and a decrease in the expression of tumor stem cell markers, suggesting a novel approach to overcome therapy resistance.

Dendritic vaccines against cytomegalovirus (CMV)
Cytomegalovirus-specific dendritic vaccines have shown promising results in improving the survival of GBM patients. In some clinical trials, patients treated with CMV-specific vaccines experienced significantly improved survival compared to conventional treatments. This immunotherapeutic approach could represent an innovative solution to improve outcomes in GBM patients.

Veliparib, TMZ and radiotherapy
The combination of veliparib with TMZ and radiotherapy has shown limited results in the treatment of GBM with an unmethylated MGMT promoter. Although the approach is safe and well tolerated, it did not lead to a significant improvement in survival compared to standard therapy, indicating that further research is needed to optimize the therapeutic combination.

DCVax-L vaccine
The DCVax-L vaccine, which uses dendritic cells loaded with tumor lysate prepared from fresh tumor collected from the patient during surgery, has been shown to significantly prolong survival in patients with GBM, showing good tolerability and a low incidence of serious adverse events. In a phase 3 clinical trial, patients treated with DCVax-L had a significantly longer median overall survival compared to the control group.

DFMO and AMXT-1501
The combination of difluoromethylornithine (DFMO) and AMXT-1501 has shown promise in reducing polyamine levels in GBM. This approach, which alters tumor metabolites and increases glutamate levels, may improve the efficacy of metabolic therapy, representing a new avenue to treat GBM through metabolic depletion.

Kinase inhibitors
The combination of kinase inhibitors and apoptosis inducers, such as Venetoclax and AZD5991, has shown strong synergies in the treatment of GBM, increasing therapeutic efficacy. However, the toxicity of these therapies must be carefully monitored, as some inhibitors can cause cardiovascular side effects.

Voyager system
The Voyager system, a low-frequency signal-based therapy, has shown promising results in the treatment of recurrent GBM, with a median survival of seven months. The system has not caused any serious device-related adverse events, making it a potentially safe option to improve treatment outcomes in GBM.

Personalized Peptide Vaccination (PPV)
Personalized peptide vaccination has shown limited results in improving overall survival in patients with recurrent GBM. Although some subgroups of patients benefited from the therapy, overall outcomes did not meet the primary endpoints of the study, indicating the need for further research to optimize this approach.

Oncolytic Viral Therapy (OVT)
Oncolytic viral therapy (OVT) has shown significant potential to improve survival in patients with recurrent GBM. Oncolytic viruses selectively target tumor cells, inducing cell lysis and stimulating an immune response against the tumor. Although further research is needed, preliminary results indicate that OVT may be an effective adjunct to the treatment of GBM.

Bone Morphogenetic Protein 4 (BMP4)
The BMP4 has been shown to reduce the self-renewal capacity of GBM cancer stem cells, promoting differentiation and increasing the efficacy of traditional therapies. This approach, which aims to reduce the cancer stem cell population, could improve the efficacy of chemotherapy and radiotherapy in GBM.

Tumor Treatment Fields (TTFs)
Tumor Treatment Fields (TTFs) have shown mixed results on the quality of life of GBM patients. Treatment leads to restrictions in daily activities for many patients. However, a significant proportion of patients expressed willingness to continue with treatment, indicating that the perceived benefits outweigh the inconveniences.

Emerging therapies for glioblastoma show considerable potential, with several innovative strategies that have demonstrated efficacy. From this review of the scientific literature it emerges that there is a lot of research underway. Glioblastoma is truly complex to treat but all these new approaches give us hope for a hopefully near future in which glioblastoma can be considered curable or at least chronic. I am increasingly convinced that in the end the solution can only come from a combination, a targeted cocktail of therapies suited to the specific glioblastoma of the patient who must always be genetically analyzed. I am also increasingly convinced that there is something wrong with the current approach to clinical trials: to be able to get to phase 3 and then replace traditional therapies, it is necessary to be more selective in patient recruitment, trying to understand for which patients the genetic profile of the tumor is such as to presuppose the effectiveness of the therapy. I realize that all this is very complex to put into practice but there have been too many years in which the standard therapy has not evolved and the results have not improved significantly: the old saying, desperate times call for desperate measures should be applied to a complex disease like GBM, leading to a different way of doing research, perhaps with the help of advances in artificial intelligence, which are very promising.