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 active-controlled 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.