Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors.
Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors.
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DOI：
10.1038/s41598-017-02483-9
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发表时间：
2017-06-01
影响因子：
4.6
通讯作者：
Shah K
中科院分区：
文献类型：
--
作者：
Zhu Y;Bassoff N;Reinshagen C;Bhere D;Nowicki MO;Lawler SE;Roux J;Shah K
开发靶向肿瘤中多种受体信号传导途径的治疗剂至关重要，因为靶向单一特异性生物标志物/途径的治疗在癌症患者中显示出有限的疗效。在这项研究中，我们广泛地表征了由表皮生长因子受体（EGFR）靶向纳米抗体（ENb）和死亡受体（DR）靶向配体TRAIL（ENb-TRAIL）组成的双功能分子。我们表明，ENb-TRAIL在来自不同癌症类型的肿瘤细胞中具有治疗功效，这些肿瘤细胞对EGFR拮抗剂或DR激动剂单一疗法均无反应。利用药理学抑制、遗传功能丧失和FRET研究，我们表明ENb-TRAIL通过ENb与EGFR的结合阻断EGFR信号传导，这反过来诱导DR 5在质膜上聚集，从而引发肿瘤细胞进行胱天蛋白酶介导的凋亡。在体内，我们使用临床相关的原发性胶质母细胞瘤原位切除模型和表达ENb-TRAIL的工程干细胞（SC），表明用包裹SC-ENb-TRAIL的合成细胞外基质（sECM）治疗可以减轻肿瘤负担并显着提高生存率。这项研究是第一个报告同时靶向不同肿瘤类型中受体介导的增殖和细胞死亡信号通路的新机制见解，并提出了一种有前途的转化为临床环境的方法。
Developing therapeutics that target multiple receptor signaling pathways in tumors is critical as therapies targeting single specific biomarker/pathway have shown limited efficacy in patients with cancer. In this study, we extensively characterized a bi-functional molecule comprising of epidermal growth factor receptor (EGFR) targeted nanobody (ENb) and death receptor (DR) targeted ligand TRAIL (ENb-TRAIL). We show that ENb-TRAIL has therapeutic efficacy in tumor cells from different cancer types which do not respond to either EGFR antagonist or DR agonist monotherapies. Utilizing pharmacological inhibition, genetic loss of function and FRET studies, we show that ENb-TRAIL blocks EGFR signalling via the binding of ENb to EGFR which in turn induces DR5 clustering at the plasma membrane and thereby primes tumor cells to caspase-mediated apoptosis. In vivo, using a clinically relevant orthotopic resection model of primary glioblastoma and engineered stem cells (SC) expressing ENb-TRAIL, we show that the treatment with synthetic extracellular matrix (sECM) encapsulated SC-ENb-TRAIL alleviates tumor burden and significantly increases survival. This study is the first to report novel mechanistic insights into simultaneous targeting of receptor-mediated proliferation and cell death signaling pathways in different tumor types and presents a promising approach for translation into the clinical setting.