Antisense therapeutics for tumor treatment: the TGF-beta2 inhibitor AP 12009 in clinical development against malignant tumors.
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.
Schlingensiepen
K H
KH
Antisense Pharma GmbH, Regensburg, Germany.
Fischer-Blass
B
B
Schmaus
S
S
Ludwig
S
S
D016375:Antisense Elements (Genetics) / Q000235:genetics* / Q000627:therapeutic use*; D018390:Gene Targeting; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000627:therapeutic use*; D013873:Thionucleotides / Q000235:genetics / Q000627:therapeutic use*; D053781:Transforming Growth Factor beta2 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
D016375:Antisense Elements (Genetics); D009838:Oligodeoxyribonucleotides; D013873:Thionucleotides; D053781:Transforming Growth Factor beta2; C525712:Trabedersen