Critical View of Novel Treatment Strategies for Glioblastoma: Failure and Success of Resistance Mechanisms by Glioblastoma Cells

Abstract

According to the invasive nature of glioblastoma, which is the most common form of malignant brain tumor, the standard care by surgery, chemo- and radiotherapy is particularly challenging. The presence of glioblastoma stem cells (GSCs) and the surrounding tumor microenvironment protects glioblastoma from recognition by the immune system. Conventional therapy concepts have failed to completely remove glioblastoma cells, which is one major drawback in clinical management of the disease. The use of small molecule inhibitors, immunomodulators, immunotherapy, including peptide and mRNA vaccines, and virotherapy came into focus for the treatment of glioblastoma. Although novel strategies underline the benefit for anti-tumor effectiveness, serious challenges need to be overcome to successfully manage tumorigenesis, indicating the significance of developing new strategies. Therefore, we provide insights into the application of different medications in combination to boost the host immune system to interfere with immune evasion of glioblastoma cells which are promising prerequisites for therapeutic approaches to treat glioblastoma patients.

Keywords: glioblastoma; immune evasion; immunotherapy; peptide and mRNA vaccines; tumor microenvironment.

FIGURE 1

A summary of major resistance mechanisms to standard treatment of glioblastoma. Main impeding factors include (A) increased active TMZ efflux by ATP-binding cassette transporters that lower the drug concentration and hence its effect. (B) Hypoxia-mediated chemoresistance caused by various hypoxia-inducible factor-1 (HIF-1) activities. (C) Direct and indirect DNA damage repair mechanisms and (D) inhibition of prodrug conversion which prevents DNA damage.

FIGURE 2

Apoptosis in glioblastoma. (A) TNF-α induces inhibition of caspases by activating NFκB upon binding to TNFR1 receptor and triggering the IKK complex to degrade the inactivating factor IκB. NFκB regulates the expression of IAPs which inhibit apoptosis. (B) Ligand binding to the receptor tyrosine kinase induces catalytic activity of PI3K and further phosphorylates PIP2 to PIP3. The phosphorylation of the Akt molecule is mediated by PDK1 and activated by PIP3, resulting in a cascade of cell survival.

FIGURE 3

Glioblastoma and the tumor microenvironment. A summary of main components of the tumor microenvironment in glioblastoma.

FIGURE 4

Integrative view of neuroinvasion and glioblastoma susceptibility to SARS-CoV-2. SARS-CoV-2 entrance depends on the attachment of the spike protein to the ACE2 receptor that is mediated by TMPRSS2 in a proteolytic manner. ACE2 is upregulated in GSCs and might increase susceptibility to SARS-CoV-2 infection.