Glioblastoma Therapy: Past, Present and Future

Abstract

Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16^ink4, TP53/MDM2/P14^arf, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood-brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials.

Keywords: glioblastoma; immunotherapy; nanotherapy; non-ionizing radiation; targeted therapy.

Figure 1

WHO diagnostic criteria for glioblastoma.

Figure 2

Origin of glioblastoma. During normal embryonic development and in the adult brain, neural stem cells (NSCs) generate glial and neuronal cells. Glioma stem cells (GSCs) arise from NSCs, astrocytes, oligodendrocytes, or glial precursor cells through the activation of oncogenic pathways (inactivation of TP53, NF1 or PTEN). GSCs are described as slow-dividing or quiescent cells, with multilineage differentiation capacity that allows them to differentiate into GB cells and cells with astrocytic, neuronal, and endothelial features and even trans-differentiation abilities. In GB tumors, there exists a dynamic equilibrium between quiescent and proliferative GSCs, and between GSC populations and their lineage-committed counterparts (differentiated non-GSC) that can also dedifferentiate into stem-lineage GSCs. Created with BioRender.com, accessed on 24 January 2024.

Figure 3

PTEN/PI3K/Akt/mTOR and RAS/RAF/MEK/ERK axis, and list of related chemotherapeutics clinically assayed against glioblastoma. Created with BioRender.com.

Figure 4

Viruses modified to infect only GB cells or to specifically induce cancer cell elimination can be delivered either directly into brain tumors or intravenously. Created with BioRender.com. Accessed on 15 January 2024.