Therapeutic strategies of recurrent glioblastoma and its molecular pathways ‘Lock up the beast’

Abstract

Glioblastoma multiforme (GBM) has a poor prognosis-despite aggressive primary treatment composed of surgery, radiotherapy and chemotherapy, median survival is still around 15 months. It starts to grow again after a year of treatment and eventually nothing is effective at this stage. Recurrent GBM is one of the most disappointing fields for researchers in which their efforts have gained no benefit for patients. They were directed for a long time towards understanding the molecular basis that leads to the development of GBM. It is now known that GBM is a heterogeneous disease and resistance comes mainly from the regrowth of malignant cells after eradicating specific clones by targeted treatment. Epidermal growth factor receptor, platelet derived growth factor receptor, vascular endothelial growth factor receptor are known to be highly active in primary and recurrent GBM through different underlying pathways, despite this bevacizumab is the only Food and Drug Administration (FDA) approved drug for recurrent GBM. Immunotherapy is another important promising modality of treatment of GBM, after proper understanding of the microenvironment of the tumour and overcoming the reasons that historically stigmatise GBM as an 'immunologically cold tumour'. Radiotherapy can augment the effect of immunotherapy by different mechanisms. Also, dual immunotherapy which targets immune pathways at different stages and through different receptors further enhances immune stimulation against GBM. Delivery of pro-drugs to be activated at the tumour site and suicidal genes by gene therapy using different vectors shows promising results. Despite using neurotropic viral vectors specifically targeting glial cells (which are the cells of origin of GBM), no significant improvement of overall-survival has been seen as yet. Non-viral vectors 'polymeric and non-polymeric' show significant tumour shrinkage in pre-clinical trials and now at early-stage clinical trials. To this end, in this review, we aim to study the possible role of different molecular pathways that are involved in GBM's recurrence, we will also review the most relevant and recent clinical experience with targeted treatments and immunotherapies. We will discuss trials utilised tyrosine receptor kinase inhibitors, immunotherapy and gene therapy in recurrent GBM pointing to the causes of potential disappointing preliminary results of some of them. Additionally, we are suggesting a possible future treatment based on recent successful clinical data that could alter the outcome for GBM patients.

Targeting Glioblastoma Stem Cells: A Review on Biomarkers, Signal Pathways and Targeted Therapy

“…The nuclear localization of stabilized β-catenin is able to abnormally activate the β-catenin signaling pathway of GSCs, and is intrinsically correlated to tumorigenesis, growth invasion in GBM ( 135 , 136 ), and the expression of MGMT, which is responsible for the resistance to TMZ ( 137 ). However, it remains highly difficult to target the Wnt/β-catenin signaling pathway owing to the serious side effects of this inhibition, as this pathway is critically related to a considerable number of physiological processes in human organs including the brain ( 138 ).…”

“…( 150 ), in 2021, SH3KBP1, a promising therapeutic target in GBM patients, was demonstrated to have the capacity to activate and modulate EGFR signaling. There are three kinds of EGFR tyrosine kinase inhibitors (TKIs) in total, including first-generation reversible small-molecule TKIs, which target EGFR and its co-receptor HER2, such as Erlotinib and Gefitinib ( 151 ), second-generation TKIs which bind irreversibly to EGFR, such as Afatinib, Neratinib and Dacomitinib ( 138 ) and third-generation irreversible inhibitors such as TKIs AZD9291 (Osimertinib), which have excellent blood–brain barrier penetration and have been shown to be effective in preclinical tests ( 152 ).…”

“…It has been found that the activation of PDGFR-signaling via a PDGF-nitric oxide (NO)-ID4-regulatory circuit ( 155 ) in humans accounts for tumorigenesis in 30% of GBM patients, and the overexpression or alterations of PDGF ligands are commonly found in GBM patients, especially in a proneural subtype of GBM, which contributes to the development of GBM and the function of GSCs, such as the self-renewal and tumor-initiating capacity to different extents among PDGFRα and PDGFRβ ( 155 ). Among several PDGF inhibitors, such as imatinib, tandutinib, AG1433, and nilotinib ( 138 , 156 ), the small molecule TKI imatinib (also known as Gleevec; Glivec; STI-571) has been demonstrated to enable the growth of GBM xenografts in vivo to inhibit and the radiosensitivity of human GSCs in vitro to increase ( 157 ), but it has no significant therapeutic effect on recurrent GBM ( 156 ).…”

Adjusting the Molecular Clock: The Importance of Circadian Rhythms in the Development of Glioblastomas and Its Intervention as a Therapeutic Strategy

“…The LOH of chromosome 10 is observed in almost 70% of GBM samples, predominantly in the primary subtype [ 23 ]. Amplification of platelet-derived growth factor receptor (PDGFR) is another genetic alteration observed in GBM tumors [ 31 ]. Lastly, IDH mutations are considered the most reliable indicator to differentiate primary from secondary GBM [ 32 , 33 , 34 , 35 , 36 ], primary GBM typically lacking IDH mutations [ 37 ].…”

Adjusting the Clock: the Importance of Circadian Rhythms in the Development of Glioblastomas and Its Intervention as a Therapeutic Strategy

“…The LOH of chromosome 10 is observed in almost 70% of GBM samples, predominantly in the primary subtype [23]. Amplification of platelet-derived growth factor receptor (PDGFR) is another genetic alteration observed in GBM tumors [31]. Lastly, IDH mutations are considered the most reliable indicator to differentiate primary from secondary GBM [32][33][34][35][36], being primary GBM those that typically lack IDH mutations [37].…”