Recent Advances in Glioma Cancer Treatment: Conventional and Epigenetic Realms

Abstract

Glioblastoma (GBM) is the most typical and aggressive form of primary brain tumor in adults, with a poor prognosis. Successful glioma treatment is hampered by ineffective medication distribution across the blood-brain barrier (BBB) and the emergence of drug resistance. Although a few FDA-approved multimodal treatments are available for glioblastoma, most patients still have poor prognoses. Targeting epigenetic variables, immunotherapy, gene therapy, and different vaccine- and peptide-based treatments are some innovative approaches to improve anti-glioma treatment efficacy. Following the identification of lymphatics in the central nervous system, immunotherapy offers a potential method with the potency to permeate the blood-brain barrier. This review will discuss the rationale, tactics, benefits, and drawbacks of current glioma therapy options in clinical and preclinical investigations.

Keywords: brain tumor; cancer; epigenetic; glioblastoma; peptide-based treatment; treatment; vaccine.

Figure 1

Schematic overview of molecules that have a vital role in GBM treatment. Growth factor receptors and intracellular signaling pathways can be activated in glioblastoma, thereby triggering gliomagenesis. Such pathways have the ability to induce tumor survival, invasiveness, proliferation, evading apoptosis, and avoiding immune surveillance [69]. EGF, VEGF, and PDGF, as well as the receptors thereof, can be blocked by small molecules and monoclonal antibodies [69]. Epigenetic process inhibitors, such as HDACis, DNMTis, BETis, and EZH2is, also have an important role to play in the treatment of patients suffering from GBM [69].

Figure 2

Tumor peptide vaccines have an immune system that activates T cells. Mature APCs may recognize and take up exogenous antigens when patients receive injections of the cancer peptide vaccines and the antigens enter the body. These are the main immunological reactions: (1) the proteasome converts proteins into small peptides that are sent to a transporter involved in the processing of antigens (TAP). The endoplasmic reticulum then binds 8–12 amino acid peptides to MHC–I (ER). (2) Following endocytosis, the antigenic polypeptides are broken down into endosomes. The resulting 12–25 amino acid peptides then interact with MHC–II, which was formed in the ER and discharged by the Golgi as vesicles. (3) The T cells become activated after recognizing and engaging the peptide-MHC complex via T cell receptors once the antigens are presented by APCs to lymphoid organs (TCRs). In the procedure, CD4+ T cells detect long polypeptides and the CD8+ T cells recognize short peptides. (4) Peptide-MHC complexes and costimulatory molecules operate as dual signals to activate immature CTLs from immature CD8+ T cells. To begin an efficient killing response, CTLs first travel to cancer locations. These cells produce a wide range of cytokines, including perforins and granzymes, as well as inflammatory mediators that dissolve target cells. (5) To maintain the expansion and proliferation of CD8+ T cells and support their antitumor effects, activated CD4+ T cells released cytokines such as IL-2, IFN-, and TNF. (6) Tumor antigens are further exposed by fragments released by tumor cell lysis, activating APCs and fostering antitumor immune responses.

Figure 3

Current strategies for immunotherapy in glioma. DCs have a direct linkage to activating CTLs and to antigen presentation, thus killing glioma cells. PD-1, CTLA-4, and IDO as immune checkpoint ligands can be activated, which in turn lead to glioma cells escaping from immune surveillance.