Lung cancer oncogenotype-selective drug target discovery

描述(申请人提供)：癌症是由细胞缺陷引起的，这种缺陷产生基因变化，导致细胞不受控制的增殖和失去 定义原点的单元格类型。由于多种基因变化的组合可能导致同一细胞类型的癌症，被归类为癌症类型的癌症，如非小细胞肺癌(NSCLC)，实际上是不同形式的疾病，对化疗的反应不同。这个项目将测试的假设是，驱动特定类型癌症(癌基因)的一组突变也将在该癌症细胞类型中产生弱点，这些弱点与正常细胞或具有不同癌基因的癌症不同。该项目将扩展试点阶段CTDD项目的工作，该项目设计了一些方法来确定癌症中由其潜在突变状态引起的脆弱性。我们的方法依赖于使用新的化学探针，因此偏向于检测可能具有治疗用途的潜在“可用药”靶标。我们将用德克萨斯大学西南分校创建的独特的天然产物库筛选一大批非小细胞肺癌和小细胞肺癌细胞系。在CTDD的试验阶段，我们已经筛选了这个文库的一个子集，其中包括全基因组的siRNA文库和200,000种化合物，使我们能够根据对这些试剂的脆弱性对肺癌小组进行分类。在这个目前的项目中，我们将识别对一组细胞株具有毒性的天然产物，这些天然产物与它们所含的突变以及它们对化疗药物和siRNA探针的敏感性有关。我们将确定感兴趣的天然产物化学探针的作用模式和分子靶标。为此，我们将使用我们开发的一种新的生物信息学工具(Fusion)，以快速将未知化学探针的活性与siRNAs、miRNAs和具有已知作用模式的化合物的活性联系起来。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图谱中发现的肿瘤中的突变进行比较，我们将确定哪些突变与每个脆弱性有关，以便这些信息可以用于临床识别可能通过针对脆弱性进行治疗的肿瘤。我们将通过确定每个漏洞来验证每个漏洞 如果针对易损性的化学探针和/或通过使用纳米颗粒将针对目标的siRNAs递送到小鼠的异种移植瘤来拮抗小鼠异种肿瘤的生长。因为我们知道我们小组中的细胞系对已知化疗药物的反应，一旦确定了功能性癌基因，我们就能够报告任何癌基因与临床批准药物的联系。虽然这个项目将从开发非小细胞肺癌和小细胞肺癌的分类方法开始，但这些方法可以应用于任何有足够大的肿瘤来源细胞系集合的癌症。我们将与CTDD合作，将我们的工具和天然产物库应用于其他类型的癌症。在UT SW，我们可以接触到越来越多的卵巢癌病例，这为未来的研究提供了机会。

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.