Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and one of the most aggressive cancers in man. Despite technological advances in surgical management, combined regimens of radiotherapy with new generation chemotherapy, the median survival for these patients is 14.6 months. This is largely due to a highly deregulated tumour genome with opportunistic deletion of tumour suppressor genes, amplification and/or mutational hyper-activation of receptor tyrosine kinase receptors. The net result of these genetic changes is augmented survival pathways and systematic defects in the apoptosis signalling machinery. The only randomised, controlled phase II trial conducted targeting the epidermal growth factor receptor (EGFR) signalling with the small molecule inhibitor, erlotinib, has showed no therapeutic benefit. Survival signalling and apoptosis resistance in GBMs can be viewed as two sides of the same coin. Targeting increased survival is unlikely to be efficacious without at the same time targeting apoptosis resistance. We have critically reviewed the literature regarding survival and apoptosis signalling in GBM, and highlighted experimental, preclinical and recent clinical trials attempting to target these pathways. Combined therapies simultaneously targeting apoptosis and survival signalling defects might shift the balance from tumour growth stasis to cytotoxic therapeutic responses that might be associated with greater therapeutic benefits.

ZFP36 expression impairs glioblastoma cell lines viability and invasiveness by targeting multiple signal transduction pathways

“…LOH on chromosome 10 is the most frequent genetic alteration in primary GBMs, occurring in 60-80% of cases. 18 Mutations in the EGF receptor result in ligand-independent constitutive tyrosine kinase activity that activates persistent downstream RAS/RAF/MAPK growth and PI3K survival signaling. 19 As regards the invasion potential of glioblastomas, extensive studies show that STAT3 (through JAK/Stat pathway) and NFκB transcription factors support migratory and invasive potential of glioblastoma cells.…”

High expression of XIAP and Bcl-2 may inhibit programmed cell death in glioblastomas

“…The upregulation of the anti-apoptotic Bcl-2 and Bcl-XL and downregulation of the pro-apoptotic Bax have been detected in recurrent GBMs, showing, in part, the resistance of GBM to TRAIL-directed treatments 18 . Our results support this hypothesis, demonstrating a significant difference in the expression of XIAP and Bcl-2, both anti-apoptotic genes, in glioblastomas, and it can suggest that the cellular death triggered by the apoptosis intrinsic pathway was inhibited in these tumors.…”

Enhanced anticancer properties of lomustine in conjunction with docosahexaenoic acid in glioblastoma cell lines

“…Patients diagnosed with glioblastoma have a median survival of approximately 15 months; 2 years after diagnosis, the survival rate is 27%. 17,41 Long-term survival rates of patients with glioblastoma have been extended with a combination treatment of radiotherapy, lomustine, and temozolomide. 11 Both progression-free and overall survival rates increased, but acute toxicity remained a significant factor.…”