Antisense Oligonucleotides in the Treatment of Malignant Gliomas

Abstract

Brain tumor therapy, despite the recent progress in neuro-oncology, in neurosurgical and neuroradiological techniques, represents a hard challenge for molecular biomedicine. Gene expression in neoplastic cells is a complex multistep process. During this event, single or multiple gene mutation can developed, resulting in clonal neoplastic cells selection. Studies on epigenetic regulation of gene expression during normal cell, tissue, and organism differentiation and evolution have, in the last decade, induced to the possibility to modulate therapeutically genome expression in cancer cells to revert or modify these toward normal cell phenotype. This kind of approach points the attention to the development of molecular therapeutic strategies based on the interaction with specific nucleotide sequences, at level of DNA or RNA, by specular nucleotide-based short molecules capable of hybridizing specific genomic DNA sequences or mRNA transcripted and translated in proteins. Antisense oligonucleotides (AONs) are synthetic stretches of DNA which hybridize with specific mRNA strands. The specificity of hybridization makes antisense method an interesting strategy to selectively modulate the expression of genes involved in tumorigenesis. The efficacy of classical anticancer strategies in high-grade gliomas is seriously limited by the lack of specific therapies against malignant cells, and the prognosis in patients affected by high-grade gliomas is still very unfavorable. Glial tumors seem to be able to create a favorable environment for the invasion of glioma cells in cerebral parenchyma when they combine with the extracellular matrix via cell surface receptors. In this chapter, we will focus on the mechanisms of action of AONs and other short nucleotide-based molecules, such as siRNA (small interference RNA), miRNA (microRNA), and long noncoding RNA, and their impact in cerebral gliomas treatment.