Targeted neuroendocrine cancer therapy using Verrucarin A

摘要 神经内分泌癌，如类癌、胰岛细胞瘤和甲状腺髓样癌 (MTC)经常转移到肝脏。尽管东北肝脏采取了各种复杂的管理策略 对于肿瘤转移，手术是唯一有可能治愈的治疗方法。迫切需要开发新的 减少NE癌症进展和激素分泌过多的治疗选择。最近，我们有 研制出一种新的针对NE癌表位的单抗--生长抑素 受体2(SSRT2)，产生标记外切体的单抗(mAb-Exo)作为递送载体，并在 高通量筛选来源于海洋海绵(Verrucarin A，VC-A)的天然化合物 抑制NE癌细胞增殖，改变恶性表型。去甲肾上腺素的初步研究 肿瘤细胞株和人移植瘤表明，我们的抗SSTR2单抗可以有效和特异地结合 SSTR2单抗与药物载体-外切体的偶联不改变对NE癌的抑制作用 靶向效能。此外，我们还发现VC-A能够诱导NE肿瘤细胞的凋亡反应 低纳摩尔浓度的细胞。为了达到较高的治疗效果，我们建议进一步研究 Vc-A的抗肿瘤作用，阐明其抑制生存途径的机制，并制定 该药物存在于配备了我们的抗SSTR2单抗的外体中。这种抗SSTR2单抗-Exo-VC-A 治疗可以选择性地将致命剂输送到NE肿瘤细胞，并将对患者的副作用降至最低。两者都有 体外NE癌细胞株和体内临床前小鼠NE肿瘤肝转移模型的建立 用于评价靶向的生物分布、耐受量、药代动力学和抗肿瘤效果 提供VC-A。如果抗癌效果将在临床前模型中得到证实，这将是第一个外体- 促进了东北癌症的靶向治疗。

ABSTRACT Neuroendocrine (NE) cancers such as carcinoids, pancreatic islet cell tumors, and medullary thyroid cancer (MTC) frequently metastasize to the liver. Despite various complex management strategies for NE liver metastases, surgery is the only treatment that offers potential for cure. There is a critical need to develop new therapeutic options to reduce NE cancer progression and excessive hormone secretion. Recently, we have developed a new monoclonal antibody (mAb) that selectively targets the NE cancers’ epitope - somatostatin receptor 2 (SSRT2), generated mAb tagged exosomes (mAb-Exo) as a delivery vehicle, and identified in the high-throughput screening a natural compound originating from marine sponges (Verrucarin A, VC-A) capable of inhibiting NE cancer cell proliferation and altering malignant phenotype. The preliminary studies using NE cancer cell lines and human xenografts indicated that our anti-SSTR2 mAb can effectively and specifically bind to NE cancer and the conjugation of SSTR2 mAb with the drug delivery vehicle – exosomes, did not change the targeting efficacy. Moreover, we have shown that VC-A is capable to induce the apoptotic response in NE cancer cells in low nanomolar concentrations. To achieve high therapeutic efficacy, we propose to further investigate the antitumor properties of VC-A, delineate the mechanisms of prosurvival pathways inhibition, and formulate the drug in exosomes which are equipped with our anti-SSTR2 mAb. Such anti-SSTR2 mAb-Exo-VC-A therapeutic can selectively deliver the lethal agent to NE tumor cells and minimize side effects to patients. Both the in vitro NE cancer cell lines and the in vivo preclinical mouse model of NE tumor liver metastases will be used to evaluate the biodistribution, tolerated doses, pharmacokinetics, and antitumor efficacy of the targeting delivered VC-A. If the anticancer efficacy will be confirmed in the preclinical model, this will be the first exosomes- facilitated targeted therapy for NE cancers.