Treatment of Malignant Gliomas with Antisense Oligonucleotides

Abstract

Antisense oligonucleotides (ODNs) are single-stranded, chemically-modified DNA-like molecules for the inhibition of gene translation by sequence-specific knockdown of mRNA through Watson–Crick hybridization. In general, their size ranges from 12 to 25 nucleotides in length, with the majority of ODNs being around 18–21 nucleotides. The natural phosphodiester backbone ODNs are rapidly degraded in biological fluids by ubiquitous nucleases. Therefore, a variety of heterocyclic modifications have been developed to strengthen base-pairing and thus stabilize the duplex formation between antisense ODN and their target mRNA. Antisense ODNs have been widely used for determining gene function, validation of drug targets and, finally, as novel therapeutics for human diseases. In this chapter, we will describe the development of antisense ODNs including their modifications, pharmacokinetics, and toxicity in animal models and humans, and their preclinical and clinical development in the therapy of human high-grade gliomas. The most advanced ODN in the therapy of high-grade gliomas is a phosphorothioate modified ODN (S-ODN), AP 12009 (trabedersen), which targets the mRNA encoding transforming growth factor beta2 (TGF-beta2). AP12009 is administered intratumorally using convection-enhanced delivery (CED). A randomized, controlled international Phase III study in recurrent or refractory anaplastic astrocytoma (SAPPHIRE) is planned to start in early 2009. Further antisense molecules targeting malignant glioma in clinical development are Affinitak, a PKC-alpha-S-ODN, and an ODN against IGF type I receptor for ex vivo use. In our opinion, antisense ODNs have potential for clinical applications in cancer patients even in a long-term perspective. They can be designed specifically against their target mRNA, are sufficiently stable in vivo and show first antitumor efficacy in human clinical trials with an excellent toxicity profile. Additionally, novel delivery techniques, like CED, may further improve their pharmacological profile making them superior to other DNA targeting strategies in humans.