New strategies for cancer drug discovery: Integrative ph

癌症药物发现的新策略：综合PH

• 批准号: 7048181
• 负责人: John N Weinstein
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7048181
• 关键词: antiAIDS agent; antineoplastics; asparaginase; camptothecin; cell growth regulation; cell line; chemical information system; chemical structure function; cytotoxicity; drug design /synthesis /production; drug discovery /isolation; drug resistance; drug screening /evaluation; gene expression; genetic mapping; messenger RNA; method development; microarray technology; molecular biology information system; neoplasm /cancer pharmacology; neoplastic cell; p53 gene /protein; pharmacokinetics; single nucleotide polymorphism; two dimensional gel electrophoresis

We are applying a combination of experimental and theoretical strategies to the discovery of new agents for treating cancer and AIDS. Since 1990, NCI has tested more than 70,000 chemically defined compounds for their ability to inhibit a panel of 60 different cancer cell lines. Growth inhibition for any single line is simply an index of cytotoxicity or cytostasis, but the patterns of 60 inhibition values encode unexpectedly rich information on mechanisms of drug action and resistance. Each compound's fingerprint pattern of activity is essentially unique among the many billions of distinguishable possibilities. We are mapping these activity patterns into molecular structure descriptors to mine NCI's Drug Information System database of more than 460,000 compounds; we are also correlating them with gene and protein expression patterns that we and our collaborators are assessing in the 60 cell lines -- in part using cDNA microarray, 2D-gel technologies, and chromosomal analyses. Overall, the databases on molecular structure, activity, and targets (>275 million numbers) constitute a major information resource that we are using (1) to generate and test hypotheses related to the cell biology of drug targets; (2) identify new lead molecules and potential targets; and (3) help set priorities for further drug development and individualization of therapy. To cite one instance, we used the information to search for compounds not dependent for activity on intact p53 suppressor gene function. Other highlights of this research include: Development of mRNA expression profile databases for cells of the NCI cancer drug discovery program. Work has been completed for a set of >8,000 genes (using 2-color EST pin-spotted arrays, in collaboration with the group of Patrick Brown at Stanford) and a set of >6,500 genes (by using oligonucleotide arrays, in collaboration with the group of Eric Lander at the Whitehead Institute). Development of a protein expression database for cells of the NCI cancer and AIDS drug discovery programs. Thus far, 1,014 spots have been indexed from 2-D polyacrylamide gels from all 60 cell types. Of these, 21 spots have been identified with particular proteins. Included are cytoarchitectural proteins, chaperonins, and molecules directly related to cell-cycle control. This project is tying together our research in molecular pharmacology and "proteome." Development of methods for identification and characterization of 2-D gel spots based on matrix-assisted laser desorption ionization (MALDI) mass spectrometry and ion trap electrospray mass spectrometry. Development and integration ( in progress) of a chromosomal description of the 60 cell lines and others. Included are spectral karyotyping (with L. Kirsch), array-based comparative genomic hybridization (with J. Gray, UCSF), and single nucleotide polymorphism identifications (1,600) (with K. Buetow). Development of the DISCOVERY program set and Clustered Image Maps, which can integrate information on a tested compound's molecular structure, pattern of activity, and possible molecular target(s). Application of DISCOVERY to identify candidate anticancer compounds not dependent on intact p53 function ("p53-inverse" compounds). . Identification from gene expression profiles of a new possible range of utility for the enzyme-drug L-asparaginase in solid tumors (with D. von Hoff). . Identification using microarrays of 3 classes of genes that change expression in response to treatment of colon cancer cell lines with the topoisomerase 1 inhibitor camptothecin. Our many collaborators include G. Li, Ph.D.; L. Shi, Ph.D.; M. Waltham, Ph.D.; Y. Fan, Ph.D.; T.G. Myers, Ph.D.; K.W. Kohn, M.D., Ph.D.; Y.G. Pommier, M.D., Ph.D.; A.J. Fornace, Jr., M.D.; S. Fan, Ph.D.; K.D. Paull, Ph.D.; D.W. Zaharevitz, Ph.D.; E.A. Sausville, M.D., Ph.D.; G.S. Johnson, Ph.D.; E. Liu, M.D., Ph.D.; Lance Miller; L.W. Rubinstein, Ph.D.; L. Kirsch, M.D., Ph.D.; K. Buetow, M.D., Ph.D.; S.E. Bates, M.D.; A.T. Fojo, M.D., Ph.D.; all of NIH. Collaborators in SAIC/NCI-FCRDC include A.P. Monks, Ph.D., and D.A. Scudiero, Ph.D. Other collaborators are N.L. Anderson, Large Scale Biology Corp.; V. Viswanadhan, Ph.D., Gensia, Inc.; B. Bunow, Ph.D.; W.W. van Osdol, Ph.D., Alza, Inc.; S.H. Friend, M.D., Ph.D., NCI/Fred Hutchinson Cancer Research Center; J.K. Buolamwini, Ph.D., University of Mississippi; P. Brown, Ph.D., D. Botstein, Ph.D., D. Ross, Ph.D., R. Tibsherani, Stanford University; E. Lander, Ph.D., T. Golub, M.D., S. Rozen, Ph.D., J. Staunton, Ph.D., H. Coller, Ph.D., et al., Whitehead Institute; J. Gray, M.D. and D. Pinkel, Ph.D., U. Calif. S.F. Cancer Institute;

我们将实验性和理论策略的组合用于发现用于治疗癌症和艾滋病的新药物。自1990年以来，NCI已经测试了70,000多种化学化合物，以抑制60种不同癌细胞系的面板。任何单线的生长抑制作用只是细胞毒性或细胞毒素的指标，但是60抑制值的模式编码了关于药物作用和抗药性机制的意外信息。在数十亿可区分的可能性中，每种化合物的活性指纹模式本质上都是独一无二的。我们将这些活性模式映射到分子结构描述中，以挖掘NCI的药物信息系统数据库，该数据库的数据库超过460,000种化合物；我们还将它们与我们和我们的合作者在60个细胞系中评估的基因和蛋白质表达模式相关联 - 部分使用cDNA微阵列，2D-GEL技术和染色体分析。总体而言，关于分子结构，活性和靶标（> 2.75亿个数字）的数据库构成了我们使用的主要信息资源（1）来生成与药物靶标细胞生物学有关的假设； （2）确定新的铅分子和潜在靶标； （3）有助于确定进一步的药物开发和个性化治疗的优先级。为了引用一个实例，我们使用该信息来搜索不依赖于完整p53抑制器基因功能活动的化合物。这项研究的其他亮点包括： 开发NCI癌症药物发现程序细胞的mRNA表达谱数据库。一组> 8,000个基因（使用2彩色的针刺阵列，与斯坦福大学的帕特里克·布朗（Patrick Brown）合作）和一组> 6,500个基因（通过使用寡核苷酸阵列，与Whitehead Institute的Eric Lander集团合作），已完成工作。 开发NCI癌细胞和AIDS药物发现程序的蛋白质表达数据库。到目前为止，已经从所有60种细胞类型的2D聚丙烯酰胺凝胶中索引了1,014个斑点。其中，已经确定了特定蛋白质的21个斑点。其中包括与细胞周期控制直接相关的细胞结构蛋白，伴侣蛋白和分子。该项目将我们在分子药理学和“蛋​​白质组”方面的研究结合在一起。 基于基质辅助激光解吸电离（MALDI）质谱法和离子陷阱电喷雾质谱法基于二-D凝胶斑点的鉴定和表征的方法的开发。 对60个细胞系和其他细胞系的染色体描述的开发和整合（正在进行）。包括光谱核分型（与L. kirsch），基于阵列的比较基因组杂交（与J. Gray，UCSF）和单核苷酸多态性鉴定（1,600）（与K. Buetow）。 开发发现程序集和聚集图像图，该图可以整合有关化合物的分子结构，活性模式和可能的分子靶标的信息。 发现发现以识别不依赖于完整p53功能的候选抗癌化合物（“ p53级”化合物）。 。从基因表达谱鉴定了实体瘤中的酶-Drug L-天冬酰胺酶的新型实用性范围（带有D. von Hoff）。 。使用3种基因的微阵列鉴定，这些基因对用拓扑异构酶1抑制剂Camptothecin治疗结肠癌细胞系改变表达。 我们的许多合作者包括G. Li博士。 L. Shi博士； M. Waltham博士； Y. Fan，博士； T.G.迈尔斯博士； K.W.医学博士Kohn博士； Y.G. M.D. Pommier博士； A.J.小福纳斯，医学博士； S. Fan，博士； K.D. Paull博士； D.W. Zaharevitz博士； E.A.医学博士Sausville博士； G.S. Johnson博士； E. Liu，M.D.，Ph.D。;兰斯·米勒（Lance Miller）； L.W.鲁宾斯坦博士； L. Kirsch，医学博士，博士；医学博士K. Buetow博士； S.E.贝茨，医学博士；在。 M.D. Fojo博士；全国卫生部。 SAIC/NCI-FRDC的合作者包括A.P. Monks，Ph.D.和D.A. Scudiero博士其他合作者是N.L.安德森，大规模生物学公司； V. Viswanadhan博士，Gensia，Inc。； B. Bunow博士； W.W. Van Osdol博士，ALZA，Inc。； S.H. NCI/Fred Hutchinson Cancer Research Center，医学博士，医学博士； J.K.密西西比大学Buolamwini博士； P. Brown博士，D。Botstein博士，D。Ross，博士，R。Tibsherani，斯坦福大学； E. Lander博士，T。Golub，M.D.，S.Rozen，Ph.D.，J.Staunton，Ph.D.，H。Coller，Ph.D. J. Gray，M.D。和D. Pinkel博士，美国加利福尼亚州。癌症研究所；