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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：
10538603
负责人：
Renata Jaskula-Sztul
金额：
$ 17.01万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10538603
关键词：
AKT inhibition 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 Induction of Apoptosis Intervention Investigation Islet Cell Tumor Islets of Langerhans Lung Measures Mediator Metastatic Neoplasm to the Liver Mitochondria Modeling Monoclonal Antibodies Mus Natural Compound Neoplasm Metastasis Neuroendocrine Tumors Neurosecretory Systems Operative Surgical Procedures Pancreas Pathway interactions Patient Isolation Patient-Focused Outcomes Patients Peptide Receptor Pharmaceutical Preparations Porifera Pre-Clinical Model Property Protein Isoforms Radiation therapy Receptor Protein-Tyrosine Kinases Recommendation 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 Visualization 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 mTOR inhibition malignant phenotype marine medullary thyroid carcinoma mouse model nanomolar neoplastic cell neuroendocrine cancer neuroendocrine phenotype novel therapeutics overexpression pre-clinical preclinical development receptor receptor binding response side effect somatostatin analog somatostatin receptor 2 subcutaneous systemic toxicity targeted delivery targeted treatment tumor 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.

抽象的神经内分泌 (NE) 癌症，例如类癌、胰岛细胞肿瘤和甲状腺髓样癌 (MTC) 经常转移至肝脏。尽管 NE 肝脏有各种复杂的管理策略对于转移，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 癌症进展和过度激素分泌的治疗选择。最近，我们有开发了一种新的单克隆抗体 (mAb)，选择性靶向 NE 癌症的表位 - 生长抑素受体 2 (SSRT2)，生成 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洋海绵的天然化合物（Verrucarin A、VC-A）抑制NE癌细胞增殖并改变恶性表型。使用NE的初步研究癌细胞系和人类异种移植物表明我们的抗 SSTR2 mAb 可以有效且特异性地结合 NE 癌症以及 SSTR2 mAb 与药物递送载体——外泌体的结合，并没有改变靶向功效。此外，我们已经证明 VC-A 能够诱导 NE 癌的细胞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 的抗肿瘤特性，描述促生存途径抑制的机制，并制定该药物位于配备有我们的抗 SSTR2 mAb 的外泌体中。此类抗SSTR2 mAb-Exo-VC-A 治疗可以选择性地将致死剂递送至NE肿瘤细胞，并最大限度地减少对患者的副作用。两个都体外NE癌细胞系和体内NE肿瘤肝转移的临床前小鼠模型将用于评估靶向药物的生物分布、耐受剂量、药代动力学和抗肿瘤功效交付了 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。