Inhibition of TGF-β2 with AP 12009 in recurrent malignant gliomas:: From preclinical to phase I/II studies
Inhibition of TGF-β2 with AP 12009 in recurrent malignant gliomas:: From preclinical to phase I/II studies
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DOI：
10.1089/oli.2006.0053
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发表时间：
2007-01-01
期刊：
影响因子：
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通讯作者：
Schlingensiepen, Karl-Hermann
中科院分区：
文献类型：
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作者：
Hau, Peter;Jachimczak, Piotr;Schlingensiepen, Karl-Hermann
已知转化生长因子-β 2（TGF-β 2）抑制对癌细胞的免疫应答，并且通过调节包括增殖、转移和血管生成的关键机制在肿瘤进展中起关键作用。针对靶向蛋白抑制，开发了TGF-β 2特异性反义寡脱氧核苷酸AP 12009。已经进行了体外实验以证明TGF-β 2抑制剂AP 12009的特异性和功效，所述体外实验采用源自患者的恶性神经胶质瘤细胞以及来自患者的外周血单核细胞（PBMC）。在临床上，反义化合物AP 12009在三个I/II期研究中评估用于治疗复发性或难治性恶性（高级别）胶质瘤WHO III或IV级患者。尽管本研究的主要设计目的不是疗效评价，但与文献数据和缓解数据相比，观察到生存期延长，这在该肿瘤适应症中非常罕见。两名患者经历了长期的肿瘤完全缓解。这些结果暗示使用AP 12009作为恶性神经胶质瘤和其他高度侵袭性的TGF-β 2过表达肿瘤的有希望的新方法的靶向TGF-β 2抑制。
Transforming growth factor-beta2 (TGF-beta 2) 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-beta 2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta 2 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-beta 2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta 2-overexpressing tumors.