Novel Targeted Anticancer Agents from Marine Cyanobacteria

来自海洋蓝藻的新型靶向抗癌剂

基本信息

批准号：
8418957
负责人：
HENDRIK LUESCH
金额：
$ 49.64万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-06 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8418957
关键词：
Address Affect Angiogenesis Inhibitors Animal Model Antineoplastic Agents Area Bioavailable Biochemical Genetics Biodiversity Biological Assay Biological Markers Cell membrane Cell surface Cells Characteristics Chemical Structure Chemical Weapons Chemicals Collection Colon Carcinoma Combined Modality Therapy Complement Cyanobacterium Cytotoxin Data Development Dolastatin 10 Down-Regulation E-Cadherin Epigenetic Process Epithelial Florida Gene Silencing Genetic Materials Genomics Growth Factor Growth Factor Receptors Guam Health Histone Deacetylase Inhibitor Human Hypoxia In Vitro Investments Lead Libraries Link Malignant Neoplasms Marines Modeling Molecular Molecular Target Monitor Mus Mutate Natural Product Drug Neoplasm Metastasis New Agents Normal Cell Northern Mariana Islands Oncogene Proteins Organism Pathway interactions Pharmaceutical Preparations Pharmacology Phenotype Play Poison Process Property Protease Inhibitor Research Resistance Resources Sampling Signal Transduction Small Interfering RNA Structure System Taxonomy Testing Therapeutic Tissues Toxin Translating Tumor Suppressor Proteins United States Virgin Islands Zebrafish adverse outcome angiogenesis anticancer research apratoxin base cancer cell cancer therapy combinatorial cytotoxicity drug discovery in vivo in vivo Model inhibitor/antagonist innovation matriptase multiple reaction monitoring mutant novel novel therapeutics outcome forecast overexpression prevent public health relevance receptor receptor expression screening tool transcription factor triple-negative invasive breast carcinoma tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Cyanobacteria are among the most ancient organisms on Earth and have evolved chemical weapons for defensive purposes, which we are exploiting for anticancer drug discovery. Our past research has exemplified that marine cyanobacteria contain compounds with exceptionally potent activity and/or possess unusual or first-in-class inhibitors with novel mechanisms of action. However, cyanobacteria are also notorious for producing toxins detrimental to human health and other general cytotoxins. Our proposal addresses main issues in natural products drug discovery, including appropriate sample selection and prioritization for those compounds with promising therapeutic potential and cancer selectivity through innovative dereplication strategies and unique complementary in vitro cellular and in vivo organismal assay sets directed towards key cancer-related pathways. Targeted pathways are related to growth factor receptor activity and angiogenesis, resistance and metastasis, all of which are major areas of concern in cancer research. We have developed new chemical, biochemical and genetic tools to specifically probe novel mechanisms of action that we recently discovered and to identify modulators of these pathways. First, we will carry out field collections of marine cyanobacteria and will subject their extracts to taxonomy- and LC-MS/MS based dereplication strategies in combination with cytotoxicity assays. Prioritized cyanobacteria will be cultured and fraction libraries generated. Second, we will implement a rational screening strategy for selective cytotoxins by assessing differential cytotoxicity of fraction libraries using various suitable human cell-based models. Specifically, we will screen for agents with selective activity against colon cancer cells over the corresponding normal cells, in a mechanistically-unbiased approach. More targeted, we will screen for antiangiogenic agents that exert their activity through a mechanism we recently validated, involving simultaneous downregulation of receptors and growth factors. Through the use of our newly created unique isogenic screening system we then aim to discover novel dual inhibitors of the transcription factors HIF-1 and HIF-2, which have promise for combination therapy with anti-angiogenic agents. Prioritized fractions will be subjected to bioassay-guided isolation and structures will be determined. Third, we have discovered and characterized a novel mechanism to prevent metastasis and developed suitable zebrafish in vivo models to screen for anti-invasive agents that modulate tumor suppressor E-cadherin expression and localization to the cell membrane when applied as single agents or in combination with a synergizing cyanobacterial compound we already discovered. Anti-invasive properties of compounds will be assessed in a new zebrafish tumor model at the single-cell level by monitoring cell dissemination, invasion and metastasis. Fourth, we will mechanistically characterize the identified selective agents to pinpoint the molecular changes induced in the cancer cell and to determine potential direct targets.

描述（由申请人提供）：蓝细菌是地球上最古老的生物之一，并且已经进化了用于防御目的的化学武器，我们正在利用抗癌药物发现。我们过去的研究表明，海洋蓝细菌含有具有异常有效活性的化合物和/或具有具有新颖的作用机理的异常或一流的抑制剂。但是，蓝细菌也因产生对人类健康和其他一般细胞毒素有害的毒素而臭名昭著。我们的提案解决了天然产品发现中的主要问题，包括通过创新的解说策略以及针对关键癌症相关途径的，具有有希望的治疗潜力和癌症选择性的适当样品选择和优先级。靶向途径与生长因子受体活性和血管生成，耐药性和转移有关，所有这些都是癌症研究中关注的主要领域。我们已经开发了新的化学，生化和遗传工具，以特别探测我们最近发现的新型作用机制，并确定这些途径的调节剂。首先，我们将进行海洋蓝细菌的现场收集，并将其提取物与分类法和LC-MS/MS基于分类法和基于细胞毒性测定的结合。将培养优先的蓝细菌并产生分数文库。其次，我们将通过使用各种合适的基于人类细胞的模型评估分数文库的差异细胞毒性来实现选择性细胞毒素的合理筛查策略。具体来说，我们将筛选在机械降低的方法中，对相应正常细胞的结肠癌细胞有选择性活性的药物。我们将通过我们最近验证的机制来筛选抗血管生成剂的抗血管生成剂，涉及受体和生长因子的同时下调。通过使用我们新创建的独特的同源筛查系统，我们旨在发现转录因子HIF-1和HIF-2的新型双重抑制剂，这有望与抗血管生成剂组合治疗。优先的分数将受到生物测定引导的隔离，结构将是决定。第三，我们发现并表征了一种新的机制，可以防止转移并开发出合适的斑马鱼在体内模型中，以筛选抗侵入性剂的抗侵入性剂，该抗侵入剂可调节肿瘤抑制剂E-钙粘蛋白的表达并定位在细胞膜上，或与单个剂或与交互式的氰基化合物合并时，我们已经发现了我们已经发现的。化合物的抗侵入性特性将通过监测细胞传播，侵袭和转移来在单细胞水平的新斑马鱼肿瘤模型中评估。第四，我们将机械地表征已鉴定的选择性剂，以查明癌细胞中诱导的分子变化并确定潜在的直接靶标。