A novel approach to target Rb mutant cancers

一种靶向 Rb 突变癌症的新方法

基本信息

批准号：
8461468
负责人：
WEI DU
金额：
$ 30.01万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8461468
关键词：
Affect Agar Antineoplastic Agents Apoptosis Biological Assay Cancer Cell Growth Cell Death Cell Death Induction Cell model Cells Cellular Stress Clinical Research Complex Development Drosophila genus Drug Targeting Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Fluorescence Resonance Energy Transfer Gefitinib Generic Drugs Genes Genetic Screening Gleevec Grant Human Lead Malignant Neoplasms Mediating Modeling Mus Mutation Normal Cell Oncogenic Pathway interactions Property Protein Tyrosine Kinase Resistance Resistance development Retinoblastoma Genes Signal Pathway Signal Transduction Staging Stress System TSC1 gene TSC2 gene Therapeutic Tissues Tumor Suppressor Genes Tumor Suppressor Proteins Tumor-Suppressor Gene Inactivation Tyrosine Kinase Inhibitor Xenograft Model base cancer cell cancer therapy cancer type cell killing fly high throughput screening in vivo inhibitor/antagonist killings lipid metabolism loss of function mutant novel strategies prevent public health relevance retinoblastoma tumor suppressor small molecule small molecule libraries success

项目摘要

DESCRIPTION (provided by applicant): The success of a cancer therapy generally depends on its ability to target certain unique requirements of the cancer cells that are distinct from those of the normal cells in the body. Current targeted cancer therapies at different stages of development mostly focus on inhibiting the deregulated oncogenic pathways. clinical studies of tyrosine kinase inhibitors such as Gefitinib and Gleevec (inhibitors of EGFR and Abl tyrosine kinases, respectively) revealed two general properties of these targeted cancer drugs: 1) they are generally only effective to a small subset of cancers with genetic alterations that make these cancers "addicted" to the deregulated oncogenic signaling being targeted; 2) cancers that are resistant to these inhibitors will eventually develop. These observations suggested the need to have large number of cancer drugs that target different features of cancer cells. In this case, different combinations of targeted cancer drugs can be used to specifically target different subsets of cancers and to prevent the development of resistant cancers. In addition to deregulated oncogenic activation, cancer cells also often have inactivation of tumor suppressor genes. However, very little effort has been devoted to develop therapeutic approaches that target such loss of tumor suppressor function in cancers. The main difficulty with targeting the loss of function tumor suppressors is the lack of straightforward approaches to either restore the lost tumor suppressor function in all the cancer cells or to specifically kill cancer cells with inactivated tumor suppressors. The Rb tumor suppressor is often inactivated in different types of cancers by mutation of the Rb gene itself, by loss of Rb expression, or by its functional inactivation. The Rb pathway is highly conserved in Drosophila. We have carried out a genetic screen in Drosophila to identify genes that can modulate the apoptosis of Rb mutant cells. Our genetic screen has led to the identification of a gene that is required specifically for preventing the apoptosis of Rb mutant cells both in developing fly tissues and in cancer cells. These observations suggest that our generic screen have led to the identification of a gene that can potentially be used as a target to specifically kill cancer cells with inactivated Rb tumor suppressor. In this grant, we will further investigate this idea to determine the mechanisms involved and to investigate the subset of cancer cells that can potentially be targeted. Furthermore we will develop assays to screen for small molecule inhibitors that can be used to specifically kill cancer cells with inactivated Rb pathway.

描述（由申请人提供）：癌症治疗的成功通常取决于其针对癌细胞不同于体内正常细胞的某些独特需求的能力。目前处于不同发展阶段的靶向癌症治疗主要集中于抑制失调的致癌途径。酪氨酸激酶抑制剂如吉非替尼和格列卫（分别是 EGFR 和 Abl 酪氨酸激酶抑制剂）的临床研究揭示了这些靶向抗癌药物的两个一般特性：1）它们通常仅对一小部分具有基因改变的癌症有效，这些癌症“沉迷”于失控的致癌信号传导； 2) 对这些抑制剂有抗药性的癌症最终将会发展。这些观察结果表明需要大量针对癌细胞不同特征的抗癌药物。在这种情况下，可以使用不同的靶向癌症药物组合来专门针对不同的癌症亚型并预防耐药癌症的发展。除了致癌激活失调之外，癌细胞还经常具有肿瘤抑制基因的失活。然而，很少有人致力于开发针对癌症中肿瘤抑制功能丧失的治疗方法。针对功能丧失的肿瘤抑制因子的主要困难是缺乏直接的方法来恢复所有癌细胞中失去的肿瘤抑制功能或用失活的肿瘤抑制因子特异性杀死癌细胞。在不同类型的癌症中，Rb 肿瘤抑制因子通常因 Rb 基因本身的突变、Rb 表达丧失或其功能失活而失活。 Rb 途径在果蝇中高度保守。我们在果蝇中进行了遗传筛选，以确定可以调节 Rb 突变细胞凋亡的基因。我们的基因筛选鉴定出了一种基因，该基因是防止发育中的果蝇组织和癌细胞中 Rb 突变细胞凋亡所必需的。这些观察结果表明，我们的通用筛选已鉴定出一种基因，该基因有可能用作用失活的 Rb 肿瘤抑制因子特异性杀死癌细胞的靶标。在这笔资助中，我们将进一步研究这个想法，以确定所涉及的机制，并研究可能成为目标的癌细胞子集。此外，我们将开发筛选小分子抑制剂的方法，这些抑制剂可用于特异性杀死 Rb 途径失活的癌细胞。