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Published on: October 27, 2014
Treatment of malignant gliomas with TGF-beta2 antisense oligonucleotides
Peter Hau1, Piotr Jachimczak, Ulrich Bogdahn
1Department of Neurology, University of Regensburg, Medical School, Regensburg, Germany. peter.hau@medbo.de
Abstract:
Antisense oligodeoxynucleotides (AS-ODNs) have been widely used to determine gene function, validate drug targets and as novel therapeutics for human diseases. In this review, we describe the development of AS-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 AS-ODN for the therapy of high-grade gliomas is a phosphorothioate-modified AS-ODN, AP 12009 (trabedersen), which targets mRNA encoding TGF-beta2. AP 12009 is administered intratumorally using convection-enhanced delivery. A series of Phase I and II clinical trials have evaluated the toxicity profile and optimal dose of the substance. A randomized, controlled international Phase III study was initiated in March 2009 and will compare trabedersen 10 microM versus conventional alkylating chemotherapy in patients with recurrent or refractory anaplastic astrocytoma after standard radio- and chemotherapy.
Insights
Antisense oligodeoxynucleotides (AS-ODNs) show promise for treating high-grade gliomas. Trabedersen (AP 12009), an AS-ODN targeting TGF-beta2, is undergoing Phase III trials for recurrent anaplastic astrocytoma.
Area of Science:
- Neuro-oncology
- Oligonucleotide Therapeutics
- Gene Silencing
Background:
- Antisense oligodeoxynucleotides (AS-ODNs) are established tools for gene function studies and drug target validation.
- AS-ODNs are being developed as novel therapeutics for various human diseases.
- High-grade gliomas remain a significant challenge in neuro-oncology.
Purpose of the Study:
- To review the development of AS-ODNs for high-grade glioma therapy.
- To discuss modifications, pharmacokinetics, toxicity, and clinical development of AS-ODNs.
- To highlight trabedersen (AP 12009) as a leading AS-ODN candidate.
Main Methods:
- Review of preclinical and clinical data on AS-ODNs in glioma therapy.
- Description of AP 12009: a phosphorothioate-modified AS-ODN targeting TGF-beta2 mRNA.
- Intratumoral administration via convection-enhanced delivery (CED).
Main Results:
- Phase I and II clinical trials established the toxicity profile and optimal dosage of AP 12009.
- AP 12009 targets mRNA encoding TGF-beta2, a key factor in glioma progression.
- A Phase III international study is comparing trabedersen to conventional chemotherapy.
Conclusions:
- Trabedersen (AP 12009) represents an advanced AS-ODN therapeutic for high-grade gliomas.
- Intratumoral CED administration of AS-ODNs is a viable delivery method.
- Ongoing Phase III trials will determine the efficacy of trabedersen in recurrent/refractory anaplastic astrocytoma.
