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：
8825339
负责人：
WEI DU
金额：
$ 31.92万
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/8825339
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 targeted cancer therapy

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）：癌症疗法的成功通常取决于其针对癌细胞某些独特需求的能力，而癌细胞与体内正常细胞的某些独特需求。当前在不同发育阶段的靶向癌症疗法主要集中在抑制失调的致癌途径上。酪氨酸激酶抑制剂（例如吉非替尼和Gleevec）（分别是EGFR和ABL酪氨酸激酶的抑制剂）的临床研究表明，这些靶向癌症药物的两个概括性：1）通常，它们仅对癌症的一小部分变化有效，这些癌症的遗传变化使这些癌症被靶向了，这些癌症是“被构成”的cancected to nercand od ogen concogen ogen concogen fornic ogen concogen的。 2）对这些抑制剂有抵抗力的癌症最终会发展。这些观察结果表明，需要大量针对癌细胞不同特征的癌症药物。在这种情况下，靶向癌症药物的不同组合可用于特异性靶向癌症的不同子集并防止抗性癌症的发展。除了失控的致癌激活外，癌细胞还经常还会灭活肿瘤抑制基因。但是，很少努力开发用于靶向癌症抑制肿瘤功能的治疗方法。靶向功能抑制剂丧失的主要困难是缺乏直接方法来恢复所有癌细胞中损失的肿瘤抑制作用功能，或者用灭活的肿瘤抑制剂特别杀死了癌细胞。 RB肿瘤抑制剂通常通过RB基因本身的突变，RB表达或通过其功能失活而在不同类型的癌症中灭活。 RB途径在果蝇中高度保守。我们已经在果蝇中进行了遗传筛选，以鉴定可以调节RB突变细胞凋亡的基因。我们的遗传筛查导致了对一个基因的鉴定，该基因是为了防止发育组织和癌细胞中RB突变细胞凋亡所必需的。这些观察结果表明，我们的通用筛选已导致鉴定一个可能被用作特异性杀死癌细胞的基因，以灭活的RB肿瘤抑制器杀死癌细胞。在这笔赠款中，我们将进一步研究这一想法，以确定涉及的机制并研究可能被靶向的癌细胞的子集。此外，我们将开发用于筛选小分子抑制剂的测定，这些抑制剂可用于特异性地杀死灭活的RB途径。