**5. Conclusion and future perspectives**

Not to mention intertumoral heterogeneity of the RTK expression, intratumoral heterogeneity, in particular the heterogeneity of amplified and mutated RTKs, presents a serious challenge to design successful single agent and/or combination therapies for patients with GBM. Thus far, clinical trials with small molecules kinase inhibitors still did not change the clinical practice in human malignant glioma [148]. GBM is one of the most challenging malignancies as featured with its infiltrating nature, recurrent tendencies and poor response to any treatment modalities, besides the intertumoral and intratumoral heterogeneity [31, 82]. The major treatment challenges contain aberrant signaling pathways, hypoxic microenvironment, phenotypic and genetic heterogeneity, GSCs and the blood-brain barrier (BBB) [1, 35, 82]. Nonetheless, aberrant RTK mutation and associated signaling pathways are hallmarks of primary GBM. As we show in this chapter, the functional interaction between RTKs and TME in GBM significantly promotes more aggressive tumor invasion, neovascularization and hypoxia, increases the number of GSCs, and adapts tumor metabolism. Thus, considering the importance of the TME in modulating cellular, molecular and epigenetic changes in a tumor cell, we propose that immunotherapy, especially vaccine-based treatment, targeting hypoxic cancer cells or HIF, and GSC-based therapies may be among the most promising strategies in GBM, in which reasonable and well-designed RTK-targeted therapy may at least partially contribute to the treatment success [31]. Dynamic treatment data measurement and personalized medicine with new imaging modalities (PET) using hypoxia radiotracers are key to delineating the hypoxic tumor regions, clinical tissue biopsy profile monitoring, and well-adjusted drug delivery systems may be rigorously applied to ensure therapeutic efficacy in GBM.
