Glioblastoma: molecular pathways, stem cells and therapeutic targets

Abstract

Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM.

Figure 1

The PI3K/AKT/mTOR pathway in GBM. The inhibitors of this pathway may contribute to an anti-tumor effect in GBM. The diagram depicts two multiprotein complexes of mTOR, mTORC1 and mTORC2. Targeting both complexes may provide better treatment options, as the recently described small molecule inhibitors appear to be more effective than analogue binding inhibitors, such as rapamycin, which targets only mTORC1. This pathway is profoundly activated in GBM due to loss of tumor suppressor PTEN (see the text for details).

Figure 2

Figure describing the treatment options for tumors containing stem cell populations (see the text and [31,42] for details).