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Targeted neuroendocrine cancer therapy using Verrucarin A

使用 Verrucarin A 进行靶向神经内分泌癌症治疗

基本信息

批准号：
10356245
负责人：
Renata Jaskula-Sztul
金额：
$ 20.83万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-09 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356245
关键词：
Animal Model Antibodies Antitumor Response Apoptosis Apoptotic Beds Binding Biodistribution Biological Assay Cancer cell line Carcinoid Tumor Cell Cycle Cell Proliferation Cell Survival Cell membrane Clinical Complex Confocal Microscopy Cytotoxic agent Development Disease Dose Drug Delivery Systems Drug Kinetics Epitopes Excision FRAP1 gene Flow Cytometry Goals Growth Hepatic Hormone secretion Human In Vitro Incidence Intervention Investigation Islet Cell Tumor Islets of Langerhans Lung Measures Mediator of activation protein Metastatic Neoplasm to the Liver Mitochondria Modeling Monoclonal Antibodies Mus Neoplasm Metastasis Neuroendocrine Tumors Neurosecretory Systems Operative Surgical Procedures Pancreas Pathway interactions Patient-Focused Outcomes Patients Peptide Receptor Pharmaceutical Preparations Porifera Pre-Clinical Model Property Protein Isoforms Radiation therapy Receptor Protein-Tyrosine Kinases Recurrence SDZ RAD SSTR2 gene Signaling Protein Somatostatin Receptor Specificity Surface System Testing Therapeutic Thyroid Gland Time Treatment Efficacy Tumor Burden Tumor Cell Line Tumor Markers Tumor-Derived Western Blotting Xenograft Model Xenograft procedure anti-cancer cancer cell cancer therapy cell growth clinical efficacy curative treatments delivery vehicle design dosage drug candidate exosome high throughput screening improved outcome in vivo in vivo Model in vivo imaging system malignant phenotype medullary thyroid carcinoma mouse model nanomolar neoplastic cell neuroendocrine cancer neuroendocrine phenotype novel therapeutics overexpression pancreatic cell line pre-clinical preclinical development receptor receptor binding response side effect somatostatin analog somatostatin receptor 2 subcutaneous systemic toxicity targeted delivery targeted treatment tumor growth tumor progression

项目摘要

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.

摘要神经内分泌（NE）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NE肝有各种复杂的管理策略，转移，手术是唯一提供治愈潜力的治疗方法。迫切需要开发新的减少NE癌症进展和过度激素分泌的治疗选择。最近我们开发了一种选择性靶向NE癌表位-生长抑素的新单克隆抗体（mAb 受体2（SSRT 2），产生mAb标记的外泌体（mAb-Exo）作为递送载体，并在高通量筛选源自海绵的天然化合物（Verrucarin A，VC-A），抑制NE癌细胞增殖和改变恶性表型。使用NE的初步研究癌细胞系和人异种移植物表明，我们的抗SSTR 2 mAb可以有效和特异性地结合对于NE癌，SSTR 2 mAb与药物递送载体-外泌体的缀合，并没有改变肿瘤细胞的增殖。靶向功效此外，我们已经表明，VC-A能够诱导NE癌细胞的凋亡反应，低纳摩尔浓度的细胞。为了达到高疗效，我们建议进一步研究 VC-A的抗肿瘤特性，描述了促生存途径抑制的机制，并制定了外泌体中的药物，其配备有我们的抗SSTR 2 mAb。这种抗SSTR 2 mAb-Exo-VC-A 治疗剂可以选择性地将致死剂递送到NE肿瘤细胞并使对患者的副作用最小化。两体外NE癌细胞系和NE肿瘤肝转移的体内临床前小鼠模型将用于评价靶向药物的生物分布、耐受剂量、药代动力学和抗肿瘤疗效。提供VC-A。如果抗癌功效将在临床前模型中得到证实，这将是第一个外泌体- 促进了NE癌症的靶向治疗。