Obstacles to Glioblastoma Treatment Two Decades after Temozolomide

Abstract

Glioblastomas are considered the most common and aggressive primary brain tumor in adults, with an average of 15 months' survival rate. The treatment is surgery resection, followed by chemotherapy with temozolomide, and/or radiotherapy. Glioblastoma must have wild-type IDH gene and some characteristics, such as TERT promoter mutation, EGFR gene amplification, microvascular proliferation, among others. Glioblastomas have great heterogeneity at cellular and molecular levels, presenting distinct phenotypes and diversified molecular signatures in each tumor mass, making it difficult to define a specific therapeutic target. It is believed that the main responsibility for the emerge of these distinct patterns lies in subcellular populations of tumor stem cells, capable of tumor initiation and asymmetric division. Studies are now focused on understanding molecular mechanisms of chemoresistance, the tumor microenvironment, due to hypoxic and necrotic areas, cytoskeleton and extracellular matrix remodeling, and in controlling blood brain barrier permeabilization to improve drug delivery. Another promising therapeutic approach is the use of oncolytic viruses that are able to destroy specifically glioblastoma cells, preserving the neural tissue around the tumor. In this review, we summarize the main biological characteristics of glioblastoma and the cutting-edge therapeutic targets that are currently under study for promising new clinical trials.

Keywords: brain tumor; cancer stem cells; chemoresistance; glioblastoma; molecular oncology.

Figure 1

Hallmarks of GBM. GBM has some striking features that contribute to its aggressive phenotype and that could be therapeutic targets. Infiltrating cells, genomic alterations, aberrant angiogenesis, immune evasion and modulation of the extratumoral environment are some of the characteristics present in the vast majority of these tumors.

Figure 2

Challenges in GBM treatment. GBM has remarkable features that make it so malignant and difficult to treat. Infiltrative cells, immune evasion, stem cells capable of repopulating the tumor mass after treatment and exchange of soluble factors and vesicles among the tumor cells, form a complex microenvironment that, together with the blood–brain barrier that hinders the entry of molecules into the brain tissue reducing the pharmacological options for the treatment of this tumor, contributes to the difficulty in the therapeutic advance of GBM.