Tyrosine Kinase Inhibitors in Adult Glioblastoma: An (Un)Closed Chapter?

Simple Summary: Glioblastoma multiforme (GBM) is the most common type of malignant brain tumor. GBM patients face a dire future, as they rarely survive longer than 15 months after diagnosis. Typically, patients undergo surgery to remove the tumor followed by combined radiotherapy and chemotherapy. However, these therapies usually extend survival only for several months, since tumors invariably regrow, which is called recurrence. Targeted therapies against specific genes that control GBM tumor-growth have been tested in clinical trials for years without success. In this article, we describe the main scientific findings leading to the testing of these targeted therapies in GBM, and discuss the potential causes behind the failure of these clinical trials. We highlight the importance of performing molecular analyses in tumors to determine the presence of those genes controlling GBM growth, before administering drugs specifically blocking their activity. In doing so clinicians could identify patients that could potentially benefit the most. Furthermore, we discuss the reasons to test these drugs in newly diagnosed patients rather than in patients under recurrence. In summary, the aim of this review is to propose alternative approaches for the design of clinical trials testing targeted therapies in GBM patients based on available scientific evidence.Glioblastoma (GBM) is the most common and lethal form of malignant brain tumor. GBM patients normally undergo surgery plus adjuvant radiotherapy followed by chemotherapy. Numerous studies into the molecular events driving GBM highlight the central role played by the Epidermal Growth Factor Receptor (EGFR), as well as the Platelet-derived Growth Factor Receptors PDGFRA and PDGFRB in tumor initiation and progression. Despite strong preclinical evidence for the therapeutic potential of tyrosine kinase inhibitors (TKIs) that target EGFR, PDGFRs, and other tyrosine kinases, clinical trials performed during the last 20 years have not led to the desired therapeutic breakthrough for GBM patients. While clinical trials are still ongoing, in the medical community there is the perception of TKIs as a lost opportunity in the fight against GBM. In this article, we review the scientific rationale for the use of TKIs targeting glioma drivers. We critically analyze the potential causes for the failure of TKIs in the treatment of GBM, and we propose alternative approaches to the clinical evaluation of TKIs in GBM patients.