TGF-β2 signaling in high-grade gliomas.

Abstract

High-grade gliomas are the most common primary tumors in the central nervous system (CNS) in adults. Despite efforts to improve treatment by combination therapies (neurosurgery, radio- and chemotherapy), high-grade glioma patients still have a grim prognosis, indicating an urgent need for new therapeutic approaches. The molecular processes of gliomagenesis are being unraveled, and novel targeted therapeutic strategies to defy high-grade gliomas are emerging. Transforming growth factor-beta (TGF-β), in particular the TGF-β2 isoform, has been identified as a key factor in the progression of malignant gliomas. TGF-β2, originally described as "glioblastoma-derived T-cell suppressor factor", is associated with the immuno-suppressed status of patients with glioblastoma, and is therefore responsible for loss of tumor immune surveillance. Elevated TGF-β2 levels in tumors and in the plasma of patients have been associated with advanced disease stage and poor prognosis. Consequently, a targeted strategy to modulate TGF-β2 signaling is highly promising. The antisense oligonucleotide trabedersen (AP 12009) that specifically blocks TGF-β2 mRNA will be the main focus of this review. In three phase I/II studies and a randomized, active-controlled dose-finding phase IIb study, trabedersen treatment of high-grade glioma patients with recurrent or refractory tumor disease led to long-lasting tumor responses and so far promising survival data. On the basis of these data the currently ongoing phase III study SAPHIRRE was initiated.

• Authors: Peter Hau, Piotr Jachimczak, Jürgen Schlaier, Ulrich Bogdahn
• Journal: Current pharmaceutical biotechnology (Curr Pharm Biotechnol) Vol. 12 Issue 12 Pg. 2150-7 (Dec 2011) ISSN: 1873-4316 [Electronic] Netherlands
• PMID: 21619538 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Oligodeoxyribonucleotides
• Thionucleotides
• Transforming Growth Factor beta2
• Trabedersen

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Brain Neoplasms (drug therapy, metabolism)
• Glioma (metabolism)
• Humans
• Oligodeoxyribonucleotides (therapeutic use)
• Thionucleotides (therapeutic use)
• Transforming Growth Factor beta2 (antagonists & inhibitors, metabolism)