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

Abstract

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.

Tyrosine Kinase Inhibitors for Glioblastoma Multiforme: Challenges and Opportunities for Drug Delivery

“…It displays considerable intratumoral heterogeneity and is characterized by genomic aberrations, high mitotic activity, microvascular proliferation, necrosis, resistance to apoptosis, and invasion into adjoining brain tissue [ 1 ]. GBM has poor prognosis with a median survival of around 12.6 months [ 4 ] as patients invariably relapse [ 5 ]. Recurrence is frequently within 2 cm of the original tumor margin, and recurrent GBM is usually not accessible to surgery and less sensitive to therapy than the initial tumor [ 5 ].…”

IDH-mutant astrocytoma with EGFR amplification—Genomic profiling in four cases and review of literature

“…Despite significant preclinical evidence for the therapeutic potential of monoclonal antibodies and tyrosine kinase inhibitors (TKIs) that target EGFR, clinical trials thus far have failed to demonstrate significant survival benefits in patients with glioblastoma, regardless of EGFR amplification and mutation status. 13 , 14 Ongoing studies continue to explore EGFR amplification status as a potentially targetable marker and our report flags an important subgroup of IDH-mutant astrocytomas that may respond to such therapy if and when it becomes actionable.…”

Identification of Immune-Related Subtypes and Construction of a Novel Prognostic Model for Bladder Urothelial Cancer

“…For instance, CTSS is a kind of lysosomal protease, the abnormal expression and activity of CTSS are related to the pathogenesis of many diseases, including cancer, cardiovascular disease, and diabetes [ 36 ], and CTSS may become a therapeutic target for lymphoma by altering the immune microenvironment of the tumor [ 37 , 38 , 39 ]. PDGFRA and PDGFRB exert a central function in the initiation and progression of many tumors, including glioblastoma, gastrointestinal stromal tumor, skin squamous cell carcinoma, and oral squamous cell carcinoma [ 40 , 41 , 42 , 43 ]. FABP6 has been reported as a potential target for inhibiting the progression of BLCA, and the mechanism may involve several aspects, such as affecting the activation of the AKT-mTOR signal and cell cycle [ 44 ].…”