Obstacles to Glioblastoma Treatment Two Decades after Temozolomide

Simple Summary Glioblastomas are the most common and aggressive brain tumors in adults, with a median survival of 15 months. Treatment is surgical removal, followed by chemotherapy and/or radiotherapy. Current chemotherapeutics do not kill all the tumor cells and some cells survive, leading to the appearance of a new tumor resistant to the treatment. These treatment-resistant cells are called tumor stem cells. In addition, glioblastoma cells have a high capacity for migration, forming new tumors in areas distant from the original tumor. Studies are now focused on understanding the molecular mechanisms of chemoresistance and controlling drug entry into the brain to improve drug performance. Another promising therapeutic approach is the use of viruses that specifically destroy glioblastoma cells, preserving the neural tissue around the tumor. In this review, we summarize the main biological features of glioblastoma and the therapeutic targets that are currently under study for new clinical trials. 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.