Glioblastoma targeted therapy: updated approaches from recent biological insights

Abstract

Glioblastoma (WHO grade IV astrocytoma) is the most frequent primary brain tumor in adults, representing a highly heterogeneous group of neoplasms that are among the most aggressive and challenging cancers to treat. An improved understanding of the molecular pathways that drive malignancy in glioblastoma has led to the development of various biomarkers and the evaluation of several agents specifically targeting tumor cells and the tumor microenvironment. A number of rational approaches are being investigated, including therapies targeting tumor growth factor receptors and downstream pathways, cell cycle and epigenetic regulation, angiogenesis and antitumor immune response. Moreover, recent identification and validation of prognostic and predictive biomarkers have allowed implementation of modern trial designs based on matching molecular features of tumors to targeted therapeutics. However, while occasional targeted therapy responses have been documented in patients, to date no targeted therapy has been formally validated as effective in clinical trials. The lack of knowledge about relevant molecular drivers in vivo combined with a lack of highly bioactive and brain penetrant-targeted therapies remain significant challenges. In this article, we review the most promising biological insights that have opened the way for the development of targeted therapies in glioblastoma, and examine recent data from clinical trials evaluating targeted therapies and immunotherapies. We discuss challenges and opportunities for the development of these agents in glioblastoma.

Keywords: biomarkers; cancer genomics; glioma; personalized medicine; precision medicine; targeted therapies.

Figure 1.

Cellular heterogeneity of RTK aberrations in glioblastoma: implications for appropriate drug targeting (adapted from Francis et al. [30]). Dynamics of the glioblastoma genome may generate or select for subclonal populations of tumor cells that are highly resistant to treatment, overall suggesting that comprehensive characterization of tumor heterogeneity is a prerequisite for the success of pharmacological inhibition of RTK alterations. Left, multiple amplifications of distinct RTK genes can be observed in non-overlapping subclonal populations from individual tumors, or within individual tumor cells. In other cases (right), tumor heterogeneity may exist as multiple alterations within a single RTK gene.

Figure 2.

Current implementation of precision medicine in glioblastoma. Practical implications of implementing precision medicine approaches in glioblastoma are depicted in this figure. Appropriate molecular profiling requires analysis of tumor tissue from the relapsed tumor. Further steps include target identification and selection, and treatment selection. Main limitations include difficulties in obtaining tumor tissue from relapse, target prioritization, and availability of optimal drugs in the context of CNS disease and related molecular alterations. This figure features pictures from ‘Servier medical art’ by Servier, used under Creative Commons Attribution 3.0 France.