Identifying determinants of chemotherapeutic response in vivo

确定体内化疗反应的决定因素

基本信息

批准号：
8111838
负责人：
Michael Hemann
金额：
$ 27.38万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-26 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8111838
关键词：
Alleles Antineoplastic Agents Apoptosis Apoptotic B-Cell Lymphomas Cancer Model Cell Death Cells Chemotherapy-Oncologic Procedure Clinical Development Doxorubicin Drug Delivery Systems Drug resistance Etiology Failure Family Family member Genes Genetic Heterogeneity Human In Vitro Lesion Lymphoma Lymphomagenesis Malignant Neoplasms Mediating Mediator of activation protein Methodology Mus Mutation Neoplasm Transplantation Oncogenes Organ Pathway interactions Pharmaceutical Preparations Phenotype Poly(ADP-ribose) Polymerases Proteins RNA Interference Regimen Relative (related person)Research Personnel Resistance Resistance development Role Screening procedure Signal Transduction Stem cell transplant Stem cells System Technology Tumor Suppression Tumor Suppressor Genes Work base cancer cell cancer therapy chemotherapy drug relapse gene function in vivo inhibitor/antagonist insight interest killings loss of function malignant breast neoplasm mouse model neoplastic cell new therapeutic target novel programs reconstitution research study response success therapy resistant tool tumor

项目摘要

DESCRIPTION (provided by applicant): Many human cancers fail to respond to chemotherapy, and cancers that initially respond frequently acquire drug resistance and relapse. While most of these anti-cancer therapies have been in clinical use for decades, very little is known about the genetic changes that promote drug resistance. As a result, current cancer treatments are applied without a clear understanding of which tumors will respond to which drugs. We propose to use RNA interference (RNAi) technologies in combination with murine stem cell and tumor transplantation systems to investigate the genetic basis for chemotherapeutic resistance. Our aim is to use these tractable mouse models to identify novel cancer drug targets, as well as strategies for tailoring existing cancer therapies to target the vulnerabilities of specific malignancies. We will use both targeted and unbiased approach to identify genes and genetic pathways that dictate the response of B cell lymphomas to well-established genotoxic chemotherapeutics. Initially, we will focus on the BH3-only family of pro-apoptotic mediators to examine the relative role of these proteins in tumor development versus chemotherapeutic response. Subsequently, we will use RNAi screening methodology to examine the role of thousands of cancer-relevant genes in the response to chemotherapy. Finally, we will target established tumor survival pathways to identify genes that, when inactivated, sensitize chemoresistant lymphomas to conventional chemotherapeutics. We expect our studies to identify critical nodes and pathways that ultimately determine the success or failure of a given chemotherapeutic.

描述（由申请人提供）：许多人类癌症无法对化学疗法做出反应，最初反应的癌症经常获得耐药性和复发。尽管这些抗癌疗法中的大多数数十年来一直在临床中使用，但对促进耐药性的遗传变化知之甚少。结果，当前的癌症治疗方法是不明确了解哪些肿瘤将对哪些药物做出反应的情况。我们建议将RNA干扰（RNAI）技术与鼠干细胞和肿瘤移植系统结合使用，以研究化学治疗抗性的遗传基础。我们的目的是使用这些可处理的小鼠模型来识别新型的癌症药物靶标，以及调整现有的癌症疗法以针对特定恶性肿瘤的脆弱性的策略。我们将使用靶向和公正方法来识别基因和遗传途径，这些基因和遗传途径决定了B细胞淋巴瘤对公认的遗传毒性化学治疗剂的反应。最初，我们将重点关注仅BH3的促凋亡介质家族，以检查这些蛋白质在肿瘤发育中的相对作用与化学治疗反应。随后，我们将使用RNAi筛查方法来检查数千个与癌症基因在对化学疗法反应中的作用。最后，我们将靶向已建立的肿瘤存活途径，以鉴定灭活后的基因，使化学耐药性淋巴瘤对常规化学疗法敏感。我们希望我们的研究能够确定最终决定给定化学治疗的成功或失败的关键节点和途径。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A DNA/HDAC dual-targeting drug CY190602 with significantly enhanced anticancer potency.

DNA/HDAC双靶向药物CY190602显着增强抗癌效力

DOI：
10.15252/emmm.201404580
发表时间：
2015-04
期刊：
EMBO molecular medicine
影响因子：
11.1
作者：
Liu C;Ding H;Li X;Pallasch CP;Hong L;Guo D;Chen Y;Wang D;Wang W;Wang Y;Hemann MT;Jiang H
通讯作者：
Jiang H

DNA damage-mediated induction of a chemoresistant niche.