Therapeutic strategies to target multiple kinases in glioblastoma

Glioblastoma (GBM), the most common primary brain tumor in adults, is one of the most aggressive human cancers associated with high mortality. Standard treatments following diagnosis include surgical resection, radiotherapy and adjunctive chemotherapy. However, almost all patients develop disease progression following this multimodal therapy. Recent understanding in genomic and molecular abnormalities in GBM has shifted the treatment paradigm towards using molecularly targeted agents. One of the most prominent targets in cancer treatment is kinases, which can be commonly targeted by small molecule inhibitors or monoclonal antibodies. Despite the initial enthusiasm in exploring kinase inhibitors for GBM, first-generation kinase inhibitors that selectively disrupt single kinases have failed to demonstrate clinical benefit in most patients with GBM. Mechanisms of resistance may include genetic heterogeneity with cross-talk and coactivation of multiple signaling pathways, upregulation of alternative signaling cascades, limited drug delivery and existence of highly-resistant cellular subpopulations such as cancer stem cells. One strategy to circumvent this challenge is to target multiple kinases by multitargeted kinase inhibitors or combinations of single targeted kinase inhibitors, both of which have been evaluated in clinical trials for GBM.