Identifying determinants of chemotherapeutic response in vivo

确定体内化疗反应的决定因素

• 批准号: 7296033
• 负责人: Michael Hemann
• 金额: $ 28.57万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-26 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7296033
• 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; Relapse; Relative (related person); Research Personnel; Resistance; Resistance development; Role; Screening procedure; Signal Transduction; Stem cells; System; Technology; Treatment Protocols; Tumor Suppression; Tumor Suppressor Genes; Work; base; cancer cell; cancer therapy; chemotherapy; gene function; in vivo; inhibitor/antagonist; insight; interest; killings; loss of function; malignant breast neoplasm; mouse model; neoplastic cell; novel; novel therapeutics; programs; reconstitution; research study; response; success; therapeutic target; therapy resistant; tool; tumor

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）：许多人类癌症对化疗没有反应，而最初有反应的癌症经常获得耐药性和复发。虽然大多数这些抗癌疗法已经在临床使用了几十年，但人们对促进耐药性的基因变化知之甚少。因此，目前的癌症治疗在没有明确了解哪种肿瘤会对哪种药物产生反应的情况下进行。我们建议将RNA干扰（RNAi）技术与小鼠干细胞和肿瘤移植系统相结合，研究化疗耐药的遗传基础。我们的目标是利用这些易处理的小鼠模型来识别新的癌症药物靶点，以及定制现有癌症治疗策略，以针对特定恶性肿瘤的脆弱性。我们将使用有针对性和无偏倚的方法来确定基因和遗传途径，这些基因和遗传途径决定了B细胞淋巴瘤对成熟的基因毒性化疗药物的反应。首先，我们将关注bh3家族的促凋亡介质，以研究这些蛋白在肿瘤发展和化疗反应中的相对作用。随后，我们将使用RNAi筛选方法来检查数千种癌症相关基因在化疗反应中的作用。最后，我们将以已建立的肿瘤生存途径为目标，以确定在失活时使化疗耐药淋巴瘤对常规化疗敏感的基因。我们希望我们的研究能够确定关键节点和途径，最终决定给定化疗的成功或失败。