Abstract
Despite remarkable advances in cancer research, patients with malignant tumors such as high-grade glioma or advanced pancreatic carcinoma still face a poor prognosis. Because of the severe morbidity and mortality of such malignant tumor types, the identification of suitable molecular drug targets for causal treatment approaches is an important area of current research. Transforming growth factor-beta 2 (TGF-β2) is an attractive target because it regulates key mechanisms of carcinogenesis, in particular immunosuppression and metastasis, and is frequently overexpressed in malignant tumors. Here we describe the development of the antisense phosphorothioate oligodeoxynucleotide trabedersen (AP 12009) which was designed for the specific inhibition of TGF-β2 biosynthesis. In vitro and in vivo experiments confirmed the mode of action, efficacy and tolerability of trabedersen and paved the way for clinical studies. In patients with high-grade glioma, intratumoral treatment with trabedersen is currently evaluated in a pivotal, randomized and activecontrolled phase III study. Intravenous application of trabedersen for the treatment of patients with advanced pancreatic carcinoma, metastasizing melanoma, or metastatic colorectal carcinoma is assessed in a currently ongoing phase I/II dose escalation study.
Keywords: Transforming growth factor beta, gene silencing, antisense oligonucleotide, cancer, immunosuppression, highgrade glioma, pancreatic cancer, molecular drug targets, metastatic colorectal carcinoma, intratumoral treatment, tumor cell growth, autoimmune or cancer diseases, mammalian genomes, latent TGF-β binding protein (LTBP)
Current Pharmaceutical Biotechnology
Title: The Antisense Oligonucleotide Trabedersen (AP 12009) for the Targeted Inhibition of TGF-β2
Volume: 12 Issue: 12
Author(s): Frank Jaschinski, Tanja Rothhammer, Piotr Jachimczak, Christian Seitz, Anneliese Schneider and Karl-Hermann Schlingensiepen
Affiliation:
Keywords: Transforming growth factor beta, gene silencing, antisense oligonucleotide, cancer, immunosuppression, highgrade glioma, pancreatic cancer, molecular drug targets, metastatic colorectal carcinoma, intratumoral treatment, tumor cell growth, autoimmune or cancer diseases, mammalian genomes, latent TGF-β binding protein (LTBP)
Abstract: Despite remarkable advances in cancer research, patients with malignant tumors such as high-grade glioma or advanced pancreatic carcinoma still face a poor prognosis. Because of the severe morbidity and mortality of such malignant tumor types, the identification of suitable molecular drug targets for causal treatment approaches is an important area of current research. Transforming growth factor-beta 2 (TGF-β2) is an attractive target because it regulates key mechanisms of carcinogenesis, in particular immunosuppression and metastasis, and is frequently overexpressed in malignant tumors. Here we describe the development of the antisense phosphorothioate oligodeoxynucleotide trabedersen (AP 12009) which was designed for the specific inhibition of TGF-β2 biosynthesis. In vitro and in vivo experiments confirmed the mode of action, efficacy and tolerability of trabedersen and paved the way for clinical studies. In patients with high-grade glioma, intratumoral treatment with trabedersen is currently evaluated in a pivotal, randomized and activecontrolled phase III study. Intravenous application of trabedersen for the treatment of patients with advanced pancreatic carcinoma, metastasizing melanoma, or metastatic colorectal carcinoma is assessed in a currently ongoing phase I/II dose escalation study.
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Jaschinski Frank, Rothhammer Tanja, Jachimczak Piotr, Seitz Christian, Schneider Anneliese and Schlingensiepen Karl-Hermann, The Antisense Oligonucleotide Trabedersen (AP 12009) for the Targeted Inhibition of TGF-β2, Current Pharmaceutical Biotechnology 2011; 12 (12) . https://dx.doi.org/10.2174/138920111798808266
DOI https://dx.doi.org/10.2174/138920111798808266 |
Print ISSN 1389-2010 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4316 |
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