AZ64 inhibits TrkB and enhances the efficacy of chemotherapy and local radiation in neuroblastoma xenografts.
AZ64 inhibits TrkB and enhances the efficacy of chemotherapy and local radiation in neuroblastoma xenografts.
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DOI：
10.1007/s00280-012-1879-x
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发表时间：
2012-09
影响因子：
3
通讯作者：
Brodeur, Garrett M.
中科院分区：
文献类型：
--
作者：
Iyer, Radhika;Varela, Carly R.;Minturn, Jane E.;Ho, Ruth;Simpson, Anisha M.;Light, Jennifer E.;Evans, Audrey E.;Zhao, Huaqing;Thress, Kenneth;Brown, Jeffrey L.;Brodeur, Garrett M.
神经母细胞瘤是一种常见的儿童肿瘤，具有临床异质性。因为它来源于交感神经母细胞，神经营养因子受体NTRK家族在神经母细胞瘤细胞的存活、生长和分化中起着不可或缺的作用。事实上，NTRK1的高表达与良好的临床特征和结果相关，而NTRK2及其配体脑源性神经营养因子（BDNF）的表达与不利的特征和结果相关。AZ64 （Astra Zeneca）是一种有效的选择性NTRK酪氨酸激酶抑制剂，可在纳摩尔浓度下阻断磷酸化。为了确定AZ64的临床前活性，我们在具有过表达ntrk2的神经母细胞瘤的异种移植模型中进行了干预试验。与药物处理动物相比，AZ64单独显著抑制肿瘤生长（肿瘤大小p = 0.0006）。此外，AZ64与常规化疗药物伊立替康和替莫唑胺（irino-temo）联合使用，与单独使用irino-temo相比，抗肿瘤疗效显著增强[肿瘤大小p < 0.0001，无事件生存（EFS） p < 0.0005]。我们还评估了AZ64联合局部放疗（RT）对神经母细胞瘤后肢异种移植模型的疗效，当动物同时接受AZ64治疗时，局部放疗的疗效显著增加（肿瘤大小p < 0.0001, EFS p = 0.0006）。我们得出结论，AZ64在体内和体外均能抑制表达ntrk的神经母细胞瘤的生长。更重要的是，它可能通过抑制NTRK2/BDNF自分泌生存途径，显著提高常规化疗的疗效以及局部RT。
Neuroblastoma is a common pediatric tumor characterized by clinical heterogeneity. Because it is derived from sympathetic neuroblasts, the NTRK family of neurotrophin receptors plays an integral role in neuroblastoma cell survival, growth, and differentiation. Indeed, high expression of NTRK1 is associated with favorable clinical features and outcome, whereas expression of NTRK2 and its ligand, brain-derived neurotrophic factor (BDNF), are associated with unfavorable features and outcome. AZ64 (Astra Zeneca) is a potent and selective inhibitor of the NTRK tyrosine kinases that blocks phosphorylation at nanomolar concentrations. To determine the preclinical activity of AZ64, we performed intervention trials in a xenograft model with NTRK2-overexpressing neuroblastomas. AZ64 alone significantly inhibited tumor growth compared to vehicle-treated animals (p = 0.0006 for tumor size). Furthermore, the combination of AZ64 with conventional chemotherapeutic agents, irinotecan and temozolomide (irino–temo), showed significantly enhanced anti-tumor efficacy compared to irino–temo alone [(p < 0.0001 for tumor size, p < 0.0005 for event-free survival (EFS)]. We also assessed the combination of AZ64 and local radiation therapy (RT) on a neuroblastoma hindlimb xenograft model, and the efficacy of local RT was significantly increased when animals were treated simultaneously with AZ64 (p < 0.0001 for tumor size, p = 0.0006 for EFS). We conclude that AZ64 can inhibit growth of NTRK-expressing neuroblastomas both in vitro and in vivo. More importantly, it can significantly enhance the efficacy of conventional chemotherapy as well as local RT, presumably by inhibition of the NTRK2/BDNF autocrine survival pathway.
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DOI：
10.1158/1078-0432.ccr-08-1815
发表时间：
2009-05-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Brodeur GM;Minturn JE;Ho R;Simpson AM;Iyer R;Varela CR;Light JE;Kolla V;Evans AE
通讯作者：
Evans AE
影响因子：
3.9
作者：
Brodeur, GM;Nakagawara, A;Evans, AE
通讯作者：
Evans, AE
影响因子：
45.3
作者：
Eggert, A;Grotzer, MA;Evans, AE
通讯作者：
Evans, AE
影响因子：
8
作者：
Dollé, L;El Yazidi-Belkoura, I;Hondermarck, H
通讯作者：
Hondermarck, H
影响因子：
2.8
作者：
George, DJ;Suzuki, H;Isaacs, JT
通讯作者：
Isaacs, JT