Targeting malignant glioma survival signalling to improve clinical outcomes

Malignant gliomas are common and aggressive brain tumours in adults. Current treatments for glioblastoma multiforme result in a poor median survival of less than 12 months. The blood-brain barrier restricts the delivery of many chemotherapies to the central nervous system, contributing to the failure of treatment. PI3K/Akt and Ras/MAPK pathways have been identified as important oncogenic pathways in these tumours. The PI3K/Akt pathway mediates cell survival and growth, whereas the Ras/MAPK pathway signals cell differentiation, proliferation and anti-apoptosis. Modern targeted therapies include antibodies to circulating growth factors and cell surface receptors, as well as inhibitors of receptor tyrosine kinases and specific intracellular signalling proteins. Monotherapy with most targeted therapies produces only modest efficacy. Better results are achieved in combination with cytotoxic chemotherapies. Future therapeutics should focus on combination therapy with small lipophilic molecules.