Current trends in targeted therapies for glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is one of the most frequently occurring tumors in the central nervous system and the most malignant tumor among gliomas. Despite aggressive treatment including surgery, adjuvant TMZ-based chemotherapy, and radiotherapy, GBM still has a dismal prognosis: the median survival is 14.6 months from diagnosis. To date, many studies report several determinants of resistance to this aggressive therapy: (1) O(6)-methylguanine-DNA methyltransferase (MGMT), (2) the complexity of several altered signaling pathways in GBM, (3) the existence of glioma stem-like cells (GSCs), and (4) the blood-brain barrier. Many studies aim to overcome these determinants of resistance to conventional therapy by using various approaches to improve the dismal prognosis of GBM such as modifying TMZ administration and combining TMZ with other agents, developing novel molecular-targeting agents, and novel strategies targeting GSCs. In this paper, we review up-to-date clinical trials of GBM treatments in order to overcome these 4 hurdles and to aim at more therapeutical effect than conventional therapies that are ongoing or are about to launch in clinical settings and discuss future perspectives.

Figure 1

RTOG 0525/EORTC 26052-22053 (dose-dense) study. The study aimed to determine if intensified TMZ (75–100 mg/m²  × 21 days, q4weeks) improves overall survival or progression-free survival compared to the standard arm (150–200 mg/m²  × 5 days, q4weeks).

Figure 2

Continuous dose-intense TMZ in recurrent malignant glioma: the RESCUE study. Ninety-one patients with GBM were prospectively divided into 3 groups according to the timing of progression during adjuvant therapy: early, extended, and rechallenge.

Figure 3

Combination with interferon-β: the JCOG0911 (INTEGRA) study. A randomized phase II clinical trial in patients with newly diagnosed GBM is under way to compare the standard-of-care regimen with the addition of IFN-β in the upfront settings.

Figure 4

Altered signaling pathways and inhibitors. Receptor tyrosine kinase (RTK), EGFR and platelet-derived growth factor receptor (PDGFR) are receptor tyrosine kinases (RTKs). In GBM, 40–60% of cases exhibit EGFR amplification and high EGFR protein expression levels. PDGFR is overexpressed at the transcriptional level. EGFR activation initiates signal transduction such as the PI3K/Akt pathway. EGFR variant III (EGFRvIII) is a constitutively activated mutation of EGFR, that is, expressed in approximately 25% of GBM cases but not in normal tissues; Sonic Hedgehog (SHH), SHH is a secreted protein critical for pattern formation in the central nervous system. SHH ligand binding to its receptors, patched homolog (PTCH) and smoothened homolog (SMO), leads to the activation of gliotactin (GLI) transcription factors that are translocated into the nuclease to regulate various cellular activities, including the maintenance of cell stemness, survival, and proliferation; NOTCH, The Notch pathway is initiated by the binding of transmembrane ligands on one cell to the notch receptors on an adjacent cell. This binding causes the γ-secretase-mediated proteolytic release of the Notch intracellular domain (NICD). Released NICD translocates into the nucleus and then turns CSL (a transcriptional factor) from a repressor to an activator, causing various effects; WNT, Wnt signals are divided into 2 different pathways: the canonical or WNT/β-catenin pathway is involved in cell fate determination and the noncanonical pathway is involved in the control of cell movement and tissue polarity [35]. Following the binding of Wnt protein to a receptor complex comprising Frizzleds/low-density lipoprotein receptor-related protein (Fz/LRP), cytoplasmic disheveled (Dvl) is phosphorylated. The phosphorylation of Dvl inhibits the activity of glycogen synthase kinase-3β (GSK-3β), elevating nonphosphorylated β-catenin levels in the cytoplasm. β-Catenin translocates into the nucleus and forms a complex with members of the T-cell transcription factor (TCF)/lymphoid enhancer-binding factor (LEF) family of transcription factors.