Whitt Jason, Hong Won S, Telange Rahul R, Lin Chee Paul, Bibb James, Beebe David J, Chen Herbert, Jaskula-Sztul Renata
Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Pathology and Laboratory Medicine and Biomedical Engineering, UW-Madison, Madison, WI, USA.
Cancer Gene Ther. 2020 Dec;27(12):898-909. doi: 10.1038/s41417-020-0167-x. Epub 2020 Feb 7.
Surgical resection is the only cure for neuroendocrine tumors (NETs). However, widespread metastases have already occured by the time of initial diagnosis in many cases making complete surgical removal impossible. We developed a recombinant heavy-chain receptor binding domain (rHCR) of botulinum neurotoxin type A that can specifically target synaptic vesicle 2 (SV2), a surface receptor abundantly expressed in multiple neuroendocrine tumors. Expression of neuroendocrine differentiation markers chromogranin A (CgA) and achaete-scute complex 1 (ASCL1) were signficantly reduced when treated with rHCR. rHCR conjugated to the antimitotic agent monomethyl auristatin E (MMAE) significantly suppressed proliferation of pancreatic carcinoid (BON) and medullary thyroid cancer cells (MZ) at concentrations of 500 and 300 nM respectively, while no growth suppression was observed in pulmonary fibroblasts and cortical neuron control cell lines. In vivo, rHCR-MMAE significantly reduced tumor volume in mouse xenografts with no observed adverse effects. These data suggest recombinant HCR (rHCR) of BoNT/A preferentially targets neuroendocrine cancer without the neurotoxicity of the full BoNT/A and that SV2 is a specific and promising target for delivering drugs to neuroendocrine tumors.
手术切除是神经内分泌肿瘤（NETs）的唯一治愈方法。然而，在许多病例中，初次诊断时就已经发生了广泛转移，使得完全手术切除变得不可能。我们开发了一种A型肉毒杆菌神经毒素的重组重链受体结合域（rHCR），它可以特异性靶向突触小泡2（SV2），这是一种在多种神经内分泌肿瘤中大量表达的表面受体。用rHCR处理后，神经内分泌分化标志物嗜铬粒蛋白A（CgA）和achaete-scute复合体1（ASCL1）的表达显著降低。与抗有丝分裂剂单甲基奥瑞他汀E（MMAE）偶联的rHCR分别在500和300 nM的浓度下显著抑制了胰腺类癌（BON）和甲状腺髓样癌细胞（MZ）的增殖，而在肺成纤维细胞和皮质神经元对照细胞系中未观察到生长抑制。在体内，rHCR-MMAE显著减小了小鼠异种移植瘤的体积，且未观察到不良反应。这些数据表明，BoNT/A的重组HCR（rHCR）优先靶向神经内分泌癌，而没有完整BoNT/A的神经毒性，并且SV2是将药物递送至神经内分泌肿瘤的一个特异性且有前景的靶点。
