Discovery of Anticancer Drugs from Cyanophytes

从蓝藻中发现抗癌药物

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：该项目的总体目标是从收集和培养的海洋氰基菌和海洋微藻中获得的新抗癌药物发现和开发具有实体瘤的选择性。考虑到人们对人的主要实体瘤的活跃性很少，对新的有效抗癌药物的需求至关重要。在这笔赠款的过程中，提议将450个分类学样本作为新型天然产品的来源获得。这些样品将采用微引导培养方法，以彻底查询其继发代谢组。从每个生物体生产了抗癌筛查的每种生物（每年超过900个测试样品）。我们采用独特而新颖的磁盘扩散测定法来鉴定初始提取物中的实体肿瘤选择性，并指导推定抗癌剂的分离。该测定法已扩展，以检查体外的7种主要实体瘤类型，然后在体内检查。我们期望每年在功能和结构上识别约6种实体瘤选择性化合物。虽然许多线索将是新的结构，但某些铅可能是已知化合物的化合物或类似物。但是，这些后一种化合物中很少有体外或体内的抗癌活性评估。我们期望通过药物开发范式吸收所有铅化合物，以确定它们是否具有临床潜力。药物发育的第一步需要15毫克的纯化合物来产生体外IC50值和浓度 - 生存的克隆生成研究。并且，体内最大耐受剂量和药代动力学信息（血浆和肿瘤水平）。该药物是用于静脉内给药的制定的，并开发了HPLC测定法以监测血清和组织水平。我们预计将在此药理阶段检查所有6年发现的体外铅化合物。将对这些数据进行分析，以确定是否应进行含有肿瘤小鼠的更昂贵的功效试验。我们预计至少有一个异种移植模型，每年将3种药物用于治疗功效试验。这样的试验可能需要进一步的收集，培养或合成的努力来获得足够的材料，估计为50-200 mg。我们希望每年找到一种在异种移植模型中具有功效的化合物，并且该铅结构将通过合成简单的类似物和自然产物的合成修饰来化学探索。在本应用之外，将在临床前和临床发育中进一步追求治疗活性的药物。公共卫生相关性：将发现抗癌药物铅，在组织培养和动物模型中确定并开发其结构，以使其对生物技术或制药公司具有吸引力，以继续发展诊所。鉴于主要实体瘤缺乏有效的抗癌药物，特别是对于转移性疾病，我们的潜在客户可能会对癌症患者产生重大积极影响。