Bai Ren-Yuan, Staedtke Verena, Rudin Charles M, Bunz Fred, Riggins Gregory J
Department of Neurosurgery (R.-Y.B., G.J.R.), Department of Neurology (V.S.); Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (F.B.); Department of Thoracic Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (C.M.R.).
Neuro Oncol. 2015 Apr;17(4):545-54. doi: 10.1093/neuonc/nou234. Epub 2014 Sep 24.
Medulloblastoma is the most common malignant brain tumor in children. Current standard treatments cure 40%-60% of patients, while the majority of survivors suffer long-term neurological sequelae. The identification of 4 molecular groups of medulloblastoma improved the clinical management with the development of targeted therapies; however, the tumor acquires resistance quickly. Mebendazole (MBZ) has a long safety record as antiparasitic in children and has been recently implicated in inhibition of various tyrosine kinases in vitro. Here, we investigated the efficacy of MBZ in various medulloblastoma subtypes and MBZ's impact on vascular endothelial growth factor receptor 2 (VEGFR2) and tumor angiogenesis.
The inhibition of MBZ on VEGFR2 kinase was investigated in an autophosphorylation assay and a cell-free kinase assay. Mice bearing orthotopic PTCH1-mutant medulloblastoma allografts, a group 3 medulloblastoma xenograft, and a PTCH1-mutant medulloblastoma with acquired resistance to the smoothened inhibitor vismodegib were treated with MBZ. The survival benefit and the impact on tumor angiogenesis and VEGFR2 kinase function were analyzed.
We determined that MBZ interferes with VEGFR2 kinase by competing with ATP. MBZ selectively inhibited tumor angiogenesis but not the normal brain vasculatures in orthotopic medulloblastoma models and suppressed VEGFR2 kinase in vivo. MBZ significantly extended the survival of medulloblastoma models derived from different molecular backgrounds.
Our findings support testing of MBZ as a possible low-toxicity therapy for medulloblastomas of various molecular subtypes, including tumors with acquired vismodegib resistance. Its antitumor mechanism may be partially explained by inhibition of tumor angiogenesis.
髓母细胞瘤是儿童最常见的恶性脑肿瘤。目前的标准治疗可治愈40%-60%的患者，而大多数幸存者会遭受长期神经后遗症。髓母细胞瘤4个分子组的鉴定随着靶向治疗的发展改善了临床管理；然而，肿瘤很快就会产生耐药性。甲苯达唑（MBZ）在儿童中作为抗寄生虫药物有很长的安全记录，并且最近在体外被证明可抑制多种酪氨酸激酶。在此，我们研究了MBZ在各种髓母细胞瘤亚型中的疗效以及MBZ对血管内皮生长因子受体2（VEGFR2）和肿瘤血管生成的影响。
在自磷酸化试验和无细胞激酶试验中研究了MBZ对VEGFR2激酶的抑制作用。用MBZ治疗携带原位PTCH1突变髓母细胞瘤同种异体移植物的小鼠、3组髓母细胞瘤异种移植物以及对 smoothened 抑制剂维莫德吉产生获得性耐药的PTCH1突变髓母细胞瘤。分析了生存获益以及对肿瘤血管生成和VEGFR2激酶功能的影响。
我们确定MBZ通过与ATP竞争来干扰VEGFR2激酶。在原位髓母细胞瘤模型中，MBZ选择性抑制肿瘤血管生成而非正常脑血管，并在体内抑制VEGFR2激酶。MBZ显著延长了源自不同分子背景的髓母细胞瘤模型的生存期。
我们的研究结果支持将MBZ作为各种分子亚型髓母细胞瘤（包括对维莫德吉产生获得性耐药的肿瘤）的一种可能的低毒性治疗方法进行测试。其抗肿瘤机制可能部分通过抑制肿瘤血管生成来解释。
