Delivery systems and molecular targets of mechanism-based therapies for GBM

Glioblastoma multiforme (GBM) is the most common malignant brain tumor of adults and is in great need of novel diagnostic and therapeutic approaches. Diagnosis is beginning to consider a tumor's genetic status and in the future may incorporate gene expression or proteomic profiles. Genetic alterations in gliomas that are being used in classification include TP53 and retinoblastoma pathway disruption, PTEN mutations, epidermal growth factor receptor amplification and 1p/19q losses. Molecular mechanisms are being exploited to treat glioblastoma multiforme. Tyrosine kinase inhibitors directed at epidermal growth factor receptor (ZD1839, OSI-774) are being explored. Farnesyltransferase inhibitors (R115777) block activation of the ras pathway and may be effective. Antagonists of the endothelin receptor (e.g., atrasentan) expressed on blood vessels may block the high degree of angiogenesis in gliomas. Tumors lacking methylthioadenosine phosphorylase are sensitive to inhibitors of de novo adenosine synthesis (SDX-102) since they lack a salvage pathway. Future goals are to tailor therapies to a tumor's molecular, proteomic or genomic status, and manage glioblastoma multiformes as in chronic diseases in a multidisciplinary clinical setting.