Antisense therapeutics for tumor treatment: the TGF-beta2 inhibitor AP 12009 in clinical development against malignant tumors.

Abstract

Overexpression of the cytokine transforming growth factor-beta 2 (TGF-beta2) is a hallmark of various malignant tumors including pancreatic carcinoma, malignant glioma, metastasizing melanoma, and metastatic colorectal carcinoma. This is due to the pivotal role of TGF-beta2 as it regulates key mechanisms of tumor development, namely immunosuppression, metastasis, angiogenesis, and proliferation. The antisense technology is an innovative technique offering a targeted approach for the treatment of different highly aggressive tumors and other diseases. Antisense oligonucleotides are being developed to inhibit the production of disease-causing proteins at the molecular level. The immunotherapeutic approach with the phosphorothioate oligodeoxynucleotide AP 12009 for the treatment of malignant tumors is based on the specific inhibition of TGF-beta2. After providing preclinical proof of concept, the safety and efficacy of AP 12009 were assessed in clinical phase I/II open-label dose-escalation studies in recurrent or refractory high-grade glioma patients. Median survival time after recurrence exceeded the current literature data for chemotherapy. Currently, phase I/II study in advanced pancreatic carcinoma, metastatic melanoma, and metastatic colorectal carcinoma and a phase IIb study in recurrent or refractory high-grade glioma are ongoing. The preclinical as well as the clinical results implicate targeted TGF-beta2 suppression as a promising therapeutic approach for malignant tumor therapy.

• Authors: K H Schlingensiepen, B Fischer-Blass, S Schmaus, S Ludwig
• Journal: Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer (Recent Results Cancer Res) Vol. 177 Pg. 137-50 ( 2008) ISSN: 0080-0015 [Print] Germany
• PMID: 18084956 (Publication Type: Journal Article)

Chemical References

• Antisense Elements (Genetics)
• Oligodeoxyribonucleotides
• Thionucleotides
• Transforming Growth Factor beta2
• Trabedersen

Topics

• Antisense Elements (Genetics) (genetics, therapeutic use)
• Gene Targeting
• Genetic Therapy
• Humans
• Male
• Middle Aged
• Neoplasms (genetics, metabolism, therapy)
• Oligodeoxyribonucleotides (genetics, therapeutic use)
• Thionucleotides (genetics, therapeutic use)
• Transforming Growth Factor beta2 (biosynthesis, genetics, metabolism)