Investigational new drugs against glioblastoma

Abstract This chapter provides a timely overview of new drugs under development for glioblastoma therapy. First, we describe the challenges to drug development that are specific to glioblastoma and inherent issues that explain the high failure rate of late phase clinical trials against these tumors. We identify measures that have the potential to overcome current challenges especially if applied early during drug development, preclinical testing, and clinical translation. We focus on agents that target tumor cell-autonomous mechanisms in primary glioblastoma that represents 90%–95% of glioblastoma diagnoses. Druggable targets in glioblastoma cells are described in a topology-based fashion including agents and strategies directed at (i) DNA, DNA repair, and DNA integrity including novel approaches to DNA alkylation, PARP, DNA protein kinase, and telomerase inhibition; (ii) epigenetic determinants of chromatin structure and gene transcription, including histone deacetylase and methylase inhibitors; (iii) modulators of cell cycle and apoptosis, including CDK4/6 inhibitors, drugs that interfere with the mitotic spindle, MDM2, Wee-1 and protein phosphatase 2A inhibitors and caspase activators; (iv) protein homeostasis, including proteasome and neddylation inhibitors; and (v) upstream cellular signaling pathways, including EGFR, PI3K/AKT/mTOR and MEK inhibitors. We also briefly discuss drug delivery and synthetic lethality approaches that may open new avenues for otherwise potentially effective drugs.