Personalized medicine for glioblastoma: current challenges and future opportunities

The failure to control glioblastoma progression is a major challenge for neuro-oncologists. Emerging data indicate that genetic and epigenetic heterogeneities within tumor cells play a dominant role in the development of resistant disease. These heterogeneities develop because driver mutations enable the proliferation of certain clones of transformed cells within the tumor microenvironment while pre-existing passenger or secondary mutations emerge from the clonal selection process during treatment. In addition, epigenetic changes provide another means of modifying the existing heterogeneous genetic background of tumor cells. These cumulative changes create challenges for the detection, characterization and treatment of glioblastomas, but new opportunities allow the development of advanced diagnostic modalities and individualized therapies. Furthermore, mutations in the epidermal growth factor receptor (EGFR) alter binding capability to targeted agents like erlotinib, rendering it inactive to block EGFR signaling. Receptor class switching and tyrosine kinase decoupling from cell cycle machineries are also mechanisms that can render tumor cells resistant to EGFR blockade. Therefore, effective therapy most likely requires the combination of personalized medicine treatment offered by targeted drugs and less specific therapies that aim at other processes within the tumor microenvironment. The goal is to take advantage of the specificity offered by targeted drugs to block proliferation of tumor cells harboring driver mutations while less specific treatments can be used against cells with passenger mutations.