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Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

TGF-β2 Signaling in High-Grade Gliomas

Author(s): Peter Hau, Piotr Jachimczak, Jurgen Schlaier and Ulrich Bogdahn

Volume 12 , Issue 12 , 2011

Page: [2150 - 2157] Pages: 8

DOI: 10.2174/138920111798808347

Price: $65

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.

Keywords: Transforming growth factor beta, signaling pathway, gliomagenesis, high-grade glioma, antisense, oligonucleotide, central nervous system (CNS), alkylating agent temozolomide, diagnosed glioblastoma, solid tumors, nuclear atypia, glioblastoma multiforme (GBM), TGF-β2 cytokines, TGF- β-responsive genes, immunocompetent cells


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