Background: Glioma is the primary cancer of the central nervous system in adults. Among gliomas, glioblastoma is the most deadly and aggressive form with an average life span of 1 to 2 years. Despite implementing the rigorous standard care involving maximal surgical removal followed by concomitant radiation and chemotherapy, the patient prognosis remains poor. Due to the infiltrative nature of glioblastoma, chemo- and radio-resistance behavior of these tumors and lack of potent chemotherapeutic drugs, treatment of glioblastoma is still a big challenge. Objective: The goal of the present review is to shed some light on the present state of novel strategies including molecular therapies, immunotherapies, nanotechnology and combination therapies for patients with glioblastoma. Methodology: Peer reviewed literature was extracted via Embase, Ovid, PubMed and Google Scholar till the year 2020. Conclusion: Insufficient effect of chemotherapies for glioblastoma is more likely because of different drug resistance mechanisms and intrinsically complex pathological characteristics. Therefore, more advancement in various therapeutic approaches such as antitumor immune response, targeting growth regulatory and drug resistance pathways, enhancing drug delivery and drug carrier systems are required in order to establish an effective treatment approach for patients with glioblastoma.

Autophagy is a process essential for cellular energy consumption, survival, and defense mechanisms. The role of autophagy in several types of human cancers has been explicitly explained; however, the underlying molecular mechanism of autophagy in glioblastoma remains ambiguous. Autophagy is thought to be a “double-edged sword”, and its effect on tumorigenesis varies with cell type. On the other hand, autophagy may play a significant role in the resistance mechanisms against various therapies. Therefore, it is of the utmost importance to gain insight into the molecular mechanisms deriving the autophagy-mediated therapeutic resistance and designing improved treatment strategies for glioblastoma. In this review, we discuss autophagy mechanisms, specifically its pro-survival and growth-suppressing mechanisms in glioblastomas. In addition, we try to shed some light on the autophagy-mediated activation of the cellular mechanisms supporting radioresistance and chemoresistance in glioblastoma. This review also highlights autophagy’s involvement in glioma stem cell behavior, underlining its role as a potential molecular target for therapeutic interventions.

Glioma stem cells (GSCs) drive the resistance mechanism in glioma tumors and mediate the suppression of innate and adaptive immune responses. Here we investigate the expression of mesenchymal-epithelial transition factor (c-Met) and Fas receptor in GSCs and their role in potentiating the tumor-mediated immune suppression through modulation of tumor infiltrating lymphocyte (TIL) population. Tumor tissues were collected from 4 patients who underwent surgery for glioblastoma. GSCs were cultured as neurospheres and evaluated for the co-expression of CD133, c-Met and FasL through flow cytometry. TILs were isolated and evaluated for the lymphocyte subset frequencies including CD3 +, CD4 +, CD8 +, regulatory T cells (FOXP3 + CD25) and microglia (CD11b + CD45) using flow cytometry. Our findings revealed that a significant population of GSCs in all four samples expressed c-Met (89–99%) and FasL (73–97%). A significantly low microglia population was found in local immune cells ranging from 3 to 5%. We did not find a statistically significant correlation between expressions of c-Met + GSC and FasL + GSC with local and systemic immune cells. This may be regarded to the small sample size. The percent c-Met + and FasL + GSC population appeared to be related to percent cytotoxic T cells, regulatory T cells and microglia populations in glioblastoma patients. Further investigation is warranted in a larger sample size.

Background: The relation between micro-RNA (miRNA) modulation and immune cell activity in high-dose radiation settings is not clearly understood. Objective: To investigate the role of stereotactic radiosurgery (SRS) in (i) the regulation of tumor-suppressor and oncogenic miRNAs as well as (ii) its effect on specific immune cell subsets in patients with metastatic brain tumors (MBT). Methods: 9 MBT patients who underwent gamma knife-based stereotactic radiosurgery (GKRS) and 8 healthy individuals were included. Serum samples were isolated at three-time intervals (before GKRS, 1 hour, and 1-month post-GKRS). Expressions of tumor-suppressor (miR-124) and oncogenic (miR-21, miR-181a, miR-23a, miR-125b, and miR-17) miRNAs were quantified by qPCR. The lymphocytic frequency (CD3+, CD4+, CD8+, CD56+, CD19+, and CD16+) was investigated by means of flow cytometry. Results: The median age was 64 years (range: 50-73 years). The median prescription dose was 20Gy (range: 16Gy-24Gy), all delivered in a single fraction. The median overall survival and progression-free survival were 7.8 months (range:1.7-14.9 months) and 6.7 months (range:1.1-11.5 months), respectively. Compared to healthy controls, baseline levels of oncogenic miRNAs were significantly higher, while tumor-suppressing miRNA levels remained markedly lower in MBT patients prior to GKRS. Following GKRS, there was a reduction in the expression of miR-21, miR-17, and miR-181a; simultaneously, increased expression increased of miR-124 was observed. No significant difference in immune cell subsets was noted post GKRSIn a similar fashion. We noted no correlation between patient characteristics, radiosurgery data, miRNA expression, and immune cell frequency. Conclusion: For this specific population with MBT disease, our data suggest that stereotactic radiosurgery may modulate the expression of circulating tumor-suppressor and oncogenic miRNAs, ultimately enhancing key anti-tumoral responses. Further evaluation with larger cohorts is warranted. conclusion: Our data showed that GKRS might regulate the expression of circulating oncogenic and tumor suppressor miRNAs towards anti-tumor effects in MBT patients. Further evaluation with larger cohorts is warranted. other: Brain metastasis, Gamma Knife radiosurgery, immune response, miRNA