A Synopsis of Biomarkers in Glioblastoma: Past and Present.

Accounting for 48% of malignant brain tumors in adults, glioblastoma has been of great interest in the last decades, especially in the biomolecular and neurosurgical fields, due to its incurable nature and notable neurological morbidity. The major advancements in neurosurgical technologies have positively influenced the extent of safe tumoral resection, while the latest progress in the biomolecular field of GBM has uncovered new potential therapeutical targets. Although GBM currently has no curative therapy, recent progress has been made in the management of this disease, both from surgical and molecular perspectives. The main current therapeutic approach is multimodal and consists of neurosurgical intervention, radiotherapy, and chemotherapy, mostly with temozolomide. Although most patients will develop treatment resistance and tumor recurrence after surgical removal, biomolecular advancements regarding GBM have contributed to a better understanding of this pathology and its therapeutic management. Over the past few decades, specific biomarkers have been discovered that have helped predict prognosis and treatment responses and contributed to improvements in survival rates.

Glioblastoma Tumor Microenvironment: An Important Modulator for Tumoral Progression and Therapy Resistance.

The race to find an effective treatment for glioblastoma (GBM) remains a critical topic, because of its high aggressivity and impact on survival and the quality of life. Currently, due to GBM's high heterogeneity, the conventional treatment success rate and response to therapy are relatively low, with a median survival rate of less than 20 months. A new point of view can be provided by the comprehension of the tumor microenvironment (TME) in pursuance of the development of new therapeutic strategies to aim for a longer survival rate with an improved quality of life and longer disease-free interval (DFI). The main components of the GBM TME are represented by the extracellular matrix (ECM), glioma cells and glioma stem cells (GSCs), immune cells (microglia, macrophages, neutrophils, lymphocytes), neuronal cells, all of them having dynamic interactions and being able to influence the tumoral growth, progression, and drug resistance thus being a potential therapeutic target. This paper will review the latest research on the GBM TME and the potential therapeutic targets to form an up-to-date strategy.

Combined Statistical Analysis of Glioblastoma Outcomes-A Neurosurgical Single-Institution Retrospective Study.

Background and Objectives: Notwithstanding the major progress in the management of cancerous diseases in the last few decades, glioblastoma (GBM) remains the most aggressive brain malignancy, with a dismal prognosis, mainly due to treatment resistance and tumoral recurrence. In order to diagnose this disease and establish the optimal therapeutic approach to it, a standard tissue biopsy or a liquid biopsy can be performed, although the latter is currently less common. To date, both tissue and liquid biopsy have yielded numerous biomarkers that predict the evolution and response to treatment in GBM. However, despite all such efforts, GBM has the shortest recorded survival rates of all the primary brain malignancies. Materials and Methods: We retrospectively reviewed patients with a confirmed histopathological diagnosis of glioblastoma between June 2011 and June 2023. All the patients were treated in the Third Neurosurgical Department of the Clinical Emergency Hospital "Bagdasar-Arseni" in Bucharest, and their outcomes were analyzed and presented accordingly. Results: Out of 518 patients in our study, 222 (42.8%) were women and 296 (57.14%) were men. The most common clinical manifestations were headaches and limb paralysis, while the most frequent tumor locations were the frontal and temporal lobes. The survival rates were prolonged in patients younger than 60 years of age, in patients with gross total tumoral resection and less than 30% tumoral necrosis, as well as in those who underwent adjuvant radiotherapy. Conclusions: Despite significant advancements in relation to cancer diseases, GBM is still a field of great interest for research and in great need of new therapeutic approaches. Although the multimodal therapeutic approach can improve the prognosis, the survival rates are still short and the recurrences are constant.

Glioblastoma Stem Cells-Useful Tools in the Battle against Cancer.

Glioblastoma stem cells (GSCs) are cells with a self-renewal ability and capacity to initiate tumors upon serial transplantation that have been linked to tumor cell heterogeneity. Most standard treatments fail to completely eradicate GSCs, causing the recurrence of the disease. GSCs could represent one reason for the low efficacy of cancer therapy and for the short relapse time. Nonetheless, experimental data suggest that the presence of therapy-resistant GSCs could explain tumor recurrence. Therefore, to effectively target GSCs, a comprehensive understanding of their biology and the survival and developing mechanisms during treatment is mandatory. This review provides an overview of the molecular features, microenvironment, detection, and targeting strategies of GSCs, an essential information required for an efficient therapy. Despite the outstanding results in oncology, researchers are still developing novel strategies, of which one could be targeting the GSCs present in the hypoxic regions and invasive edge of the glioblastoma.

Updated Insights on EGFR Signaling Pathways in Glioma.

Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood-brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.

Evaluation of Single and Combined Temozolomide and Doxorubicin Treatment Responses in Low- and High-Grade Glioma In Vitro.

BACKGROUND: Astrocytoma, the most common type of glioma, can histologically be low or high grade. Treatment recommendations for astrocytic tumors are based on the histopathological and molecular phenotype. For grade 2 astrocytoma, the combination of radiotherapy and adjuvant chemotherapy with procarbazine, lomustine, and vincristine (PCV) is better than radiotherapy alone. Temozolomide (TMZ) is being increasingly recognized as a replacement for PCV in brain tumor therapy, due to the lower myelotoxicity. TMZ is currently a well-established first-line treatment for grade 3 astrocytoma, grade 4 astrocytoma, and glioblastoma and it is also sporadically used for grade 2 astrocytoma. However, TMZ faces multiple challenges such as adverse effects and drug resistance. METHODS: In this study, we compared the cytotoxic effect induced by TMZ and doxorubicin (DOXO), alone and in combination, on a low-grade astrocytoma cell line (AC1B) and a high-grade glioma cell line (GB1B). RESULTS: We found that TMZ and DOXO, each produced a cytotoxic effect in monotherapy. GB1B cell line was more sensitive to the treatment than AC1B cells, at a 7- and 10-day exposure to the DOXO. However, when the duration of the treatment was extended to 14 days, GB1B cells became more resistant to DOXO treatment, compared to AC1B cells. Regarding the treatment with TMZ, GB1B exhibited greater resistance to TMZ compared to AC1B, across all studied intervals and the resistance to treatment of GB1B increased with longer exposure time. However, in combined therapy, the drugs did not exert a synergistic effect on any astrocytic cell line. CONCLUSIONS: The current data suggest that both TMZ and DOXO exhibit efficient therapeutic effects on low- and high-grade glioma cells. However, no synergistic effect was observed for combined therapy.

The Effect of Β-Arrestin2 Overexpression Regarding Viability and Temozolomide Treatment in High-Grade Glioma Cells.

The ß-arrestins (ß-arr) family are proteins that regulate the signaling and trafficking of various G protein-coupled receptors. Out of the four members, ß-arr 1 and 2 have been proven as essential actors behind different processes that lead to the progression of cancer as cell proliferation, migration, invasion and metastasis. In addition to this, these proteins are also capable of transmitting anti-apoptotic signals, influence tumor growth rate and drug resistance. Several studies have demonstrated that ß-arr 2 overexpression corelates with an impaired overall survival and also showed that it may mediate multidrug resistance in certain types of cancer. In the current study we analyzed the effect of ß-arr 2 overexpression on proliferation and how it affects Temozolomide (TMZ) response on the CL2:6 High Grade Glioma (HGG) cell line. We observed contradictory results after transfection, with ß-arr 2 overexpressing cells having a superior proliferation rate after 24 and 48h, when compared to untransfected cells, while the opposite was noted after 72h. In terms of response to TMZ, we observed a similar contradictory pattern with modest differences between doses being observed at 24h, while the smallest and largest doses in our experiment produced opposite effects after 48h and 72h. This further underscores the scarcity of information regarding the exact roles and the importance of ß-arrs in the intrinsic mechanisms which govern cancer cells.

Combined Effects of Doxorubicin and Temozolomide in Cultured Glioblastoma Cells.

The oncological field benefits of extensive medical research and various types of cancer notice improvements, however glioblastoma multiforme remains one of the deadliest cancers in humans with virtually no advance in survival and clinical outcome. Temozolomide, the FDA approved drug for glioblastoma, faces numerous challenges such as resistance and side effects. To overcome these challenges, many combination therapies are currently studied. The present study analyses the effects of temozolomide in combination with doxorubicin on a glioblastoma cell line. Our results showed that both drugs displayed a cytotoxic effect on the studied cells in single administration (55% for 100µM temozolomide at 14 days, 53% for 100µM doxorubicin at 14 days), but without a synergistic effect in dual therapy. Although the results failed to produce the expected effect, they propose new research perspectives in the future.