Beck Olaf, Paret Claudia, Russo Alexandra, Burhenne Jürgen, Fresnais Margaux, Steimel Kevin, Seidmann Larissa, Wagner Daniel-Christoph, Vewinger Nadine, Lehmann Nadine, Sprang Maximilian, Backes Nora, Roth Lea, Neu Marie Astrid, Wingerter Arthur, Henninger Nicole, Malki Khalifa El, Otto Henrike, Alt Francesca, Desuki Alexander, Kindler Thomas, Faber Joerg
Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Cancers (Basel). 2020 Mar 26;12(4):793. doi: 10.3390/cancers12040793.
Osteosarcoma (OS) is the second most common cause of cancer-related death in pediatric patients. The insulin-like growth factor (IGF) pathway plays a relevant role in the biology of OS but no IGF targeted therapies have been successful as monotherapy so far. Here, we tested the effect of three IGF specific inhibitors and tested ceritinib as an off-target inhibitor, alone or in combination with dasatinib, on the proliferation of seven primary OS cells. Picropodophyllin, particularly in combination with dasatinib and the combination ceritinib/dasatinib were effective in abrogating the proliferation. The ceritinib/dasatinib combination was applied to the primary cells of a 16-year-old girl with a long history of lung metastases, and was more effective than cabozantinib and olaparib. Therefore, the combination was used to treat the patient. The treatment was well tolerated, with toxicity limited to skin rush and diarrhea. A histopathological evaluation of the tumor after three months of therapy indicated regions of high necrosis and extensive infiltration of macrophages. The extension of the necrosis was proportional to the concentration of dasatinib and ceritinib in the area, as analysed by an ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). After the cessation of the therapy, radiological analysis indicated a massive growth of the patient's liver metastases. In conclusion, these data indicate that the combination of ceritinib/dasatinib is safe and may be used to develop new therapy protocols.
骨肉瘤（OS）是儿科患者癌症相关死亡的第二大常见原因。胰岛素样生长因子（IGF）通路在OS生物学中发挥着相关作用，但迄今为止，尚无IGF靶向疗法作为单一疗法取得成功。在此，我们测试了三种IGF特异性抑制剂的效果，并测试了色瑞替尼作为非靶向抑制剂单独或与达沙替尼联合使用对七种原发性OS细胞增殖的影响。鬼臼苦素，特别是与达沙替尼联合使用以及色瑞替尼/达沙替尼联合使用，在消除增殖方面有效。色瑞替尼/达沙替尼联合用药应用于一名有长期肺转移病史的16岁女孩的原代细胞，比卡博替尼和奥拉帕尼更有效。因此，该联合用药被用于治疗该患者。治疗耐受性良好，毒性仅限于皮疹和腹泻。治疗三个月后对肿瘤进行的组织病理学评估显示有高坏死区域和巨噬细胞广泛浸润。通过超高效液相色谱-串联质谱仪（UPLC-MS/MS）分析，坏死范围与该区域达沙替尼和色瑞替尼的浓度成正比。治疗停止后，放射学分析表明患者肝转移灶大量生长。总之，这些数据表明色瑞替尼/达沙替尼联合用药是安全的，可用于制定新的治疗方案。
