Targeting Glioblastoma: The Current State of Different Therapeutic Approaches

Abstract

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.

Methods: Peer-reviewed literature was retrieved 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.

Keywords: Glioblastoma; immunotherapy; microRNA; nano-therapy; targeted therapy; viral therapy..

Fig. (1)

miRNA biogenesis begins in the nucleus of the cell with cleavage of pri-miRNA to produce stemloop structure pre-miRNA by Drosha and DiGeorge Syndrome Critical Region 8 (DGCR8). Exportin5/Ran/GTP complex transports pre-miRNA to the cytoplasm. Dicer and TRBP (RNA-binding co-factor of Dicer) process the pre-miRNAs to miRNA duplex, which subsequently in the presence of helicase enzyme forms single-stranded mature miRNA. Later, mature miRNA complexes with RNA-induced silencing complex (RISC) in which Argonaute-2 (AGO-2) protein plays a central role. The seed region of the miRNAs recognizes and binds the 3'UTR of the target mRNAs and may affect the expression of genes through mRNA cleavage, translational repression, or translational activation. Current miRNA based inhibition therapies or replacement therapies that implement mimic miRNAs and miRNA expression vectors. MiRNAs inhibitory therapies involve suppressing the expression levels of oncogenic miRNAs on the contrary, replacement therapies involve the overexpression of tumor suppressor miRNAs through the expression of vector based delivery systems. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (2)

Present immunotherapy strategies for glioblastoma: Oncolytic virus (OV) therapy, involves engineered designed to target tumor cells only. OV infection leads to tumor cell lysis and consequently triggers the immune response via dendritic cells (DC). In addition to that, some OV induce the release of immunoregulatory molecules like interleukin-15 (IL-15), interleukin-18 (IL-18), interferon (IFN) and interleukin-12 (IL-12) which can trigger immune system via DC, natural killer cells (NK) and macrophages (Φ). In adaptive immune response, DCs presents tumor antigens, virus particles or immunoregulatory molecules to Cytotoxic T lymphocytes (CTLs) via Major Histocompatibility Complex (MHC) class II and T cell receptor (TCR) on T cells or via surface receptors CD86 or CD80 on DC cells and CD28 on T cells. CTLs are responsible for destroying glioblastoma cells that are presenting antigens located on MHC class I molecules, through TCR and CD3 interactions. Immune checkpoint regulation involving Cytotoxic T lymphocyte ligandcytotoxic T lymphocyte protein (CTLA-4) complex and programmed cell death 1 ligand 1 (PD-L1) receptor which located on the cell surface of glioblastoma cells can interact with programmed cell death 1 receptor (PD-1) located on CTLs play a crucial role in the inhibition of activated lymphocytes. Also, transforming growth factor-beta (TGF-β) from tumor cells inhibit CTL function making it a therapeutic target. Checkpoint inhibition therapy is based on averting this ligand binding by specific monoclonal antibodies/inhibitors which bind to these receptors. Genetically engineered CD8+ T cells (CAR T), namely anti-HER2, anti- IL-13Ra2 and anti-EGFRvIII are designed to target respective tumor specific antigens HER2, IL-13Ra2 and EGFRvIII located on the cancer cell surfaces and eliciting tumor immune response. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (3)

Schematic representations of novel therapeutic nano-conjugate systems for targeted therapies against glioblastoma. (A higher resolution / colour version of this figure is available in the electronic copy of the article).