Lung cancer oncogenotype-selective drug target discovery

肺癌癌基因型选择性药物靶点发现

基本信息

批准号：
8657424
负责人：
JOHN B MACMILLAN
金额：
$ 68.52万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2013-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657424
关键词：
Advanced Development Affect Analytical Chemistry Animals Binding Biochemical Bioinformatics Biological Biological Assay Biological Factors Biological Markers Cancer Biology Cancer Etiology Cancer Intervention Cancer cell line Cell Line Cell Proliferation Cells Characteristics Chemical Actions Chemicals Chemistry Chromatography Clinical Oncology Collection Combined Modality Therapy Crystallography Data Defect Development Disease Drug Targeting Drug resistance Enrollment Fermentation Fractionation Frequencies Future Gene Expression Genetic Genetic Epistasis Genomics Goals Growth Hand Hereditary Disease Human Investigation Knowledge Libraries Link Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Methods MicroRNAs Molecular Molecular Target Mus Mutation Natural Products Chemistry Non-Small-Cell Lung Carcinoma Normal Cell Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phase Proteins Reagent Reporting Research Small Interfering RNA Structure Testing The Cancer Genome Atlas Therapeutic Therapeutic Uses Time Toxic effect Tumor-Derived Work Xenograft procedure base cancer cell cancer therapy cancer type cell type chemotherapeutic agent chemotherapy combat combination cancer therapy design drug discovery exome sequencing genome sequencing genome-wide high throughput screening interest killings nanoparticle new therapeutic target novel public health relevance research study response screening small molecule therapeutic target tool tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Cancer is caused by cellular defects that produce genetic changes that cause uncontrolled cell proliferation and the loss of the characteristics that define the cell type of origin. As many combinations of genetic changes can cause cancer in the same cell type, cancers that are classified as a cancer type, such as Non-Small Cell Lung Cancer (NSCLC), are really different forms of disease that respond differently to chemotherapy. The hypothesis that this project will test is that the set of mutations that drive a particular typ of cancer (an oncogenotype), will also create weaknesses in that cancer cell type that are not shared with normal cells or cancers with a different oncogenotype. This project will extend the work of a pilot phase CTDD project that has designed methods to identify vulnerabilities in cancers that are caused by their underlying mutational status. Our methods rely upon the use of novel chemical probes and thus are biased towards detecting potentially "druggable" targets likely to be of therapeutic use. We will screen a large panel of NSCLC and SCLC cell lines with a unique natural products library created at UT Southwestern. In the pilot phase of the CTDD we have screened a subset of this library with genome wide siRNA libraries and 200,000 chemical compounds, allowing us to categorize the lung cancer panel according to vulnerabilities to these reagents. In this current project we will identify natural products that ae toxic to groups of cell lines that are related by the mutations they contain and their sensitivitie to chemotherapeutic agents and siRNA probes. We will identify the mode of action and molecular targets of natural product chemical probes of interest. To do this, we will employ a new bioinformatics tool (FUSION) we have developed to rapidly link the activity of an unknown chemical probe to the activity of siRNAs, miRNAs and compounds with known mode of action. By sequencing the exome of each cell line and comparing mutations found in cell lines to the mutations found in tumors by The Cancer Genome Atlas, we will determine which mutations are linked to each vulnerability, so that this information can be used clinically to identify tumors tht might be treated by targeting the vulnerability. We will validate each vulnerability by determining if the growth of tumor xenografts in mice is antagonized by a chemical probe that targets the vulnerability and/or by delivering siRNAs against the target to xenografts in mice, using nanoparticle delivery. Because we know the response of the cell lines in our panel to known chemotherapeutic drugs, we will be able to report any linkage of an oncogenotype to clinically approved drugs as soon as the functional oncogenotype is defined. Although this project will begin by developing methods to categorize NSCLC and SCLC, these methods can be applied to any cancer for which there is a sufficiently large collection of tumor-derived cell lines. We wil work with the CTDD to apply our tools and natural products library to other types of cancer. At UT SW we have access to a growing panel of ovarian cancers that provide an opportunity for future study.

描述（由申请人提供）：癌症是由细胞缺陷引起的，产生遗传变化，导致不受控制的细胞增殖以及特征的丧失定义原点的细胞类型。由于遗传变化的许多组合可能在同一细胞类型中引起癌症，因此被分类为癌症类型的癌症（例如非小细胞肺癌（NSCLC））确实是对化学疗法反应不同的疾病形式。该项目将测试的假设是，驱动特定癌症类型的突变集（一种癌基因型）也会在该癌细胞类型中造成弱点，而该癌细胞类型与未与正常细胞或具有不同型植物型的正常细胞或癌症共享。该项目将扩展一个试验阶段CTDD项目的工作，该项目设计了通过其基本突变状态引起的癌症中漏洞的方法。我们的方法依赖于新型化学探针的使用，因此偏向于检测可能使用治疗的潜在“可药”靶标。我们将筛选一大批NSCLC和SCLC细胞系，并在UT Southwestern创建一个独特的天然产品库。在CTDD的试点阶段，我们已经筛选了该库的一个子集，其中具有基因组宽的siRNA库和200,000个化合物，从而使我们可以根据对这些试剂的漏洞对肺癌面板进行分类。在当前的项目中，我们将鉴定出AE有毒的天然产物，这些天然产物对细胞系有毒，这些细胞系与它们所包含的突变以及它们对化学治疗剂和siRNA探针的敏感性相关。我们将确定感兴趣的自然产物化学探针的作用方式和分子靶标。为此，我们将采用一种新的生物信息学工具（Fusion），我们开发了将未知化学探针的活性与siRNA，miRNA和化合物的活性迅速联系起来，并具有已知的作用方式。通过对每个细胞系的外显子组进行测序，并将细胞系中发现的突变与癌症基因组地图集在肿瘤中发现的突变进行比较，我们将确定哪些突变与每个脆弱性有关，以便可以在临床上使用该信息来识别可以通过靶向脆弱性来治疗的肿瘤。我们将通过确定来验证每个漏洞如果使用纳米粒子递送，将小鼠肿瘤异种移植物的生长通过针对脆弱性和/或靶向靶标针对异种移植物的靶标的siRNA和/或的化学探针拮抗。因为我们知道面板中细胞系对已知化学治疗药物的反应，所以我们将能够在定义功能性致癌性型后立即报告癌基型与临床认可的药物的任何联系。尽管该项目将首先开发用于对NSCLC和SCLC进行分类的方法，但这些方法可以应用于任何肿瘤衍生的细胞系足够大的癌症。我们将与CTDD合作，将我们的工具和天然产品库应用于其他类型的癌症。在UT SW，我们可以使用越来越多的卵巢癌小组，这些癌症为将来的研究提供了机会。