Challenges and Perspectives of Standard Therapy and Drug Development in High-Grade Gliomas

Abstract

Despite their low incidence rate globally, high-grade gliomas (HGG) remain a fatal primary brain tumor. The recommended therapy often is incapable of resecting the tumor entirely and exclusively targeting the tumor leads to tumor recurrence and dismal prognosis. Additionally, many HGG patients are not well suited for standard therapy and instead, subjected to a palliative approach. HGG tumors are highly infiltrative and the complex tumor microenvironment as well as high tumor heterogeneity often poses the main challenges towards the standard treatment. Therefore, a one-fit-approach may not be suitable for HGG management. Thus, a multimodal approach of standard therapy with immunotherapy, nanomedicine, repurposing of older drugs, use of phytochemicals, and precision medicine may be more advantageous than a single treatment model. This multimodal approach considers the environmental and genetic factors which could affect the patient's response to therapy, thus improving their outcome. This review discusses the current views and advances in potential HGG therapeutic approaches and, aims to bridge the existing knowledge gap that will assist in overcoming challenges in HGG.

Keywords: anaplastic astrocytoma; anaplastic oligodendroglioma; chemotherapy; glioblastoma; high-grade glioma; immunotherapy; nanoparticles; oligodendroglioma; phytochemicals; radiotherapy.

Figure 1

Schematic depiction of Tmz mode of action. Tmz undergoes spontaneous hydrolysis intracellularly to form monomethyl triazene 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). MTIC then hydrolyzed to form 5-aminoimidazole- 4-carboxamide, which later converts into methylhydrazine [52]. Methyldiazonium, an active cation, then methylates the nucleobases, preferentially N⁷ position of guanine (N⁷-MeG; 70%), guanine rich site and to a certain extend at N³ adenine (N³-MeA; 9%) and O⁶ guanine residues (O⁶-MeG; 6%) [59,60]. This results in the formation of nicks in the DNA resulting in apoptosis and cell cycle arrest at the G₂/M phase [60,61].

Figure 2

Mechanisms of Tmz resistance. (a) The expression of MGMT along with successful DNA repair mechanisms: (b) mismatch repair; (c) Base excision repair resulting in survival as GBM tumors leading to chemoresistance.

Figure 3

Phytochemicals as potential adjuvants in HGG. Phytochemicals from different classes modulate various signaling pathways in human HGG tumor cells that promote cell cycle arrestment, inhibit cell proliferation, invasion, migration, and promote cell death.