Hau Peter, Jachimczak Piotr, Schlingensiepen Reimar, Schulmeyer Frank, Jauch Tanya, Steinbrecher Andreas, Brawanski Alexander, Proescholdt Martin, Schlaier Jürgen, Buchroithner Johanna, Pichler Josef, Wurm Gabriele, Mehdorn Maximilian, Strege Rainer, Schuierer Gerhard, Villarrubia Victoria, Fellner Franz, Jansen Olav, Straube Thorsten, Nohria Virinder, Goldbrunner Michael, Kunst Mechthild, Schmaus Susanne, Stauder Gerhard, Bogdahn Ulrich, Schlingensiepen Karl-Hermann
Department of Neurology, University of Regensburg, Germany.
Oligonucleotides. 2007 Summer;17(2):201-12. doi: 10.1089/oli.2006.0053.
Transforming growth factor-beta2 (TGF-beta2) is known to suppress the immune response to cancer cells and plays a pivotal role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. For targeted protein suppression the TGF-beta2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta2 inhibitor AP 12009 employing patient-derived malignant glioma cells as well as peripheral blood mononuclear cells (PBMCs) from patients. Clinically, the antisense compound AP 12009 was assessed in three Phase I/II-studies for the treatment of patients with recurrent or refractory malignant (high-grade) glioma WHO grade III or IV. Although the study was not primarily designed as an efficacy evaluation, prolonged survival compared to literature data and response data were observed, which are very rarely seen in this tumor indication. Two patients experienced long-lasting complete tumor remissions. These results implicate targeted TGF-beta2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta-2-overexpressing tumors.
已知转化生长因子-β2（TGF-β2）可抑制对癌细胞的免疫反应，并通过调节包括增殖、转移和血管生成在内的关键机制在肿瘤进展中发挥关键作用。为了实现靶向蛋白抑制，研发了TGF-β2特异性反义寡脱氧核苷酸AP 12009。已进行体外实验，以采用患者来源的恶性胶质瘤细胞以及患者的外周血单个核细胞（PBMC）来证明TGF-β2抑制剂AP 12009的特异性和有效性。在临床上，反义化合物AP 12009在三项I/II期研究中用于治疗复发性或难治性WHO III级或IV级恶性（高级别）胶质瘤患者。尽管该研究并非主要设计用于疗效评估，但与文献数据相比观察到生存期延长，且出现了反应数据，这在该肿瘤适应症中非常罕见。两名患者经历了持久的完全肿瘤缓解。这些结果表明，使用AP 12009靶向抑制TGF-β2是一种用于恶性胶质瘤和其他高度侵袭性、TGF-β2过表达肿瘤的有前景的新方法。
