权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
8495624
负责人：
JOHN B MACMILLAN
金额：
$ 70.23万
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/8495624
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 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，这种细胞缺陷会产生基因变化，导致不受控制的细胞增殖和细胞特征的丧失