Discovery of Anticancer Drugs from Cyanophytes

从蓝藻中发现抗癌药物

• 批准号: 7736146
• 负责人: FREDERICK Augustus VALERIOTE
• 金额: $ 41.17万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736146
• 关键词: Algae; Animal Model; Antineoplastic Agents; Applications Grants; Aquaculture; Biological Assay; Biological Factors; Biology; Biomass; Brain; Breast; California; Cancer Center; Cancer Patient; Characteristics; Chemical Structure; Chemicals; Chemistry; Clinic; Clinical; Collaborations; Collection; Coupled; Crude Extracts; Cyanobacterium; Data; Detection; Development; Diffusion; Disease; Dose; Drug Administration Schedule; Drug Kinetics; Epigenetic Process; Evaluation; Foundations; Fractionation; Gene Cluster; Genes; Goals; Grant; Health system; High Pressure Liquid Chromatography; In Vitro; Inhibitory Concentration 50; Institution; Laboratories; Lead; Malignant neoplasm of lung; Marines; Materials Testing; Maximum Tolerated Dose; Methods; Modification; Molecular; Monitor; Mus; Oceanography; Organism; Ovarian; Pancreas; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phylogenetic Analysis; Plasma; Program Development; Regulatory Pathway; Relative (related person); Research; Route; Sampling; Scheme; Screening procedure; Serum; Solid; Solid Neoplasm; Source; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staging; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Universities; Water; Xenograft Model; analog; anticancer activity; base; cancer cell; cytotoxicity; drug development; drug discovery; efficacy trial; in vitro Assay; in vivo; innovation; interest; intravenous administration; marine natural product; microbial; novel; pre-clinical; programs; public health relevance; rectal; therapeutic effectiveness; tissue culture; tumor

DESCRIPTION (provided by applicant): The overall goal of this project is the discovery and development of new anticancer drugs with solid tumor selectivity from leads obtained from collected and cultured marine cyanobacteria and marine microalgae. The need for new and effective anticancer drugs is critical given the paucity of ones active against the major solid tumors in people. Over the course of this grant, 450 taxonomically diverse samples are proposed to be obtained as a source of novel natural products. Micro-elicitation culture methods will be employed on a set of these samples to thoroughly query their secondary metabolomes. Nine fractions plus crude extract are produced from each organism for the anticancer screen (over 900 test samples per year). We employ a unique and novel disk diffusion assay to both identify solid tumor selectivity in the initial extracts and also to direct the isolation of the putative anticancer agent. The assay has been expanded to examine the 7 major solid tumor types in vitro and then in vivo. We expect to both functionally and structurally identify about 6 solid tumor selective compounds per year. While many of the leads will be novel structures, some of the leads may be known compounds or analogues of known compounds; however, very few of these latter compounds will have been evaluated for anticancer activity either in vitro or in vivo. We expect to take all of our lead compounds through a drug development paradigm so as to determine whether they have clinical potential. The first step of drug development requires 15 mg of pure compound to produce in vitro IC50 values and concentration-survival clonogenic studies; and, in vivo maximum tolerated dose and pharmacokinetic information (plasma and tumor levels). The drug is formulated for intravenous administration and an HPLC assay is developed to monitor serum and tissue levels. We expect that all 6 of the yearly discovered in vitro lead compounds will be examined in this pharmacologic phase. These data will be analyzed to determine whether the more expensive efficacy trials in tumor-bearing mice should be undertaken. We expect 3 drugs per year will go to therapeutic efficacy trial in at least one xenograft model. Such a trial will likely require a further collection, culturing or synthetic efforts to gain sufficient material, estimated at 50 - 200 mg. We expect to find one compound per year that has efficacy in the xenograft models, and this lead structure will be chemically explored through synthesis of simple analogs and synthetic modification of the natural product. Therapeutically active drugs will be pursued further in preclinical and clinical development outside of this application. PUBLIC HEALTH RELEVANCE: Anticancer drug leads will be discovered, their structure determined and developed both in tissue culture and animal models to a stage where they should be attractive to either Biotech or Pharmaceutical companies to continue with their development towards the clinic. Given the lack of effective anticancer drugs for the major solid tumors, especially for metastatic disease, our leads can have a significant positive impact on the cancer patient.

描述（申请人提供）：本项目的总体目标是从采集和培养的海洋蓝藻和海洋微藻中获得的先导化合物中发现和开发具有实体瘤选择性的新型抗癌药物。鉴于对人类主要实体瘤有效的抗癌药物的缺乏，对新的有效抗癌药物的需求至关重要。在此期间，450个分类学上不同的样品被提议作为新的天然产品的来源。将对一组这些样本采用微量诱导培养方法，以彻底查询其次级代谢组。从每种生物体中产生9个馏分和粗提物用于抗癌筛选（每年超过900个测试样品）。我们采用了一种独特的和新颖的磁盘扩散试验，以确定实体瘤的选择性在初始提取物，并直接分离的推定抗癌剂。该试验已扩展到在体外和体内检查7种主要实体瘤类型。我们预计每年在功能和结构上鉴定出约6种实体瘤选择性化合物。虽然许多先导化合物将是新结构，但一些先导化合物可能是已知化合物或已知化合物的类似物;然而，很少有这些后一种化合物将在体外或体内评价抗癌活性。我们希望通过药物开发模式来研究我们所有的先导化合物，以确定它们是否具有临床潜力。药物开发的第一步需要15 mg纯化合物，以产生体外IC 50值和浓度-存活克隆形成研究;以及体内最大耐受剂量和药代动力学信息（血浆和肿瘤水平）。该药物配制用于静脉给药，并开发了HPLC测定法以监测血清和组织水平。我们预计，每年发现的所有6种体外先导化合物都将在本药理学阶段进行检查。这些数据将被分析，以确定是否应该在荷瘤小鼠中进行更昂贵的疗效试验。我们预计每年将有3种药物在至少一种异种移植模型中进行疗效试验。这样的试验可能需要进一步的收集、培养或合成努力以获得足够的材料，估计为50 - 200 mg。我们希望每年能找到一种在异种移植模型中有效的化合物，这种先导结构将通过简单类似物的合成和天然产物的合成修饰进行化学探索。将在本申请之外的临床前和临床开发中进一步研究治疗活性药物。公共卫生关系：抗癌药物先导将被发现，它们的结构将在组织培养和动物模型中被确定和开发到一个阶段，在这个阶段，它们应该对生物技术公司或制药公司有吸引力，以继续向临床发展。由于缺乏有效的抗癌药物的主要实体瘤，特别是转移性疾病，我们的领导人可以有一个显着的积极影响癌症患者。