Novel Targeted Anticancer Agents from Marine Cyanobacteria

来自海洋蓝藻的新型靶向抗癌剂

• 批准号: 8633022
• 负责人: HENDRIK LUESCH
• 金额: $ 43.6万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 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/8633022
• 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

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，已经进化出用于防御目的的化学武器，我们正在利用它们来发现抗癌药物。我们过去的研究已经证明，海洋蓝藻含有化合物具有非常有效的活性和/或拥有不寻常的或一流的抑制剂与新的作用机制。然而，蓝细菌也因产生对人类健康有害的毒素和其他一般细胞毒素而臭名昭著。我们的提案解决了天然产物药物发现中的主要问题，包括通过创新的去复制策略和独特的互补体外细胞和体内生物测定集，针对关键癌症相关途径，对具有治疗潜力和癌症选择性的化合物进行适当的样品选择和优先级排序。靶向通路与生长因子受体活性和血管生成、耐药和转移有关，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，生物化学和遗传工具，专门探测我们最近发现的新的作用机制，并确定这些途径的调节剂。首先，我们将进行海洋蓝藻的实地收集，并将其提取物进行分类和LC-MS/MS为基础的去复制策略与细胞毒性试验相结合。优先蓝藻将被培养和馏分库产生。其次，我们将实施一个合理的筛选策略，选择性细胞毒素，通过评估不同的细胞毒性的馏分库使用各种合适的人类细胞为基础的模型。具体来说，我们将筛选 在机械上无偏的方法中，具有相对于相应的正常细胞对结肠癌细胞的选择性活性的药剂。更有针对性的，我们将筛选抗血管生成剂，通过我们最近验证的机制发挥其活性，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等基因筛选系统，我们的目标是发现新的转录因子HIF-1和HIF-2的双重抑制剂，这有希望与抗血管生成剂的联合治疗。优先级部分将进行生物测定引导的分离， 测定第三，我们已经发现并表征了一种新的机制，以防止转移，并开发了合适的斑马鱼体内模型，以筛选抗侵袭剂，调节肿瘤抑制因子E-钙粘蛋白的表达和定位到细胞膜时，作为单一的代理商或与协同蓝藻化合物，我们已经发现的组合。将在新的斑马鱼肿瘤模型中，通过监测细胞播散、侵袭和转移，在单细胞水平上评估化合物的抗侵袭特性。第四，我们将机械地表征所鉴定的选择性试剂，以查明在癌细胞中诱导的分子变化，并确定潜在的直接靶点。