Identifying determinants of chemotherapeutic response in vivo

描述(申请人提供)：许多人类癌症对化疗没有反应，最初有反应的癌症经常获得抗药性并复发。虽然这些抗癌疗法中的大多数已经在临床上使用了几十年，但人们对促进耐药性的基因变化知之甚少。因此，目前的癌症治疗是在没有明确了解哪些肿瘤对哪些药物有反应的情况下应用的。我们建议将RNA干扰(RNAi)技术与小鼠干细胞和肿瘤移植系统结合起来，研究化疗耐药的遗传基础。我们的目标是使用这些易处理的小鼠模型来识别新的抗癌药物靶点，以及针对特定恶性肿瘤的脆弱性定制现有癌症治疗方法的策略。我们将使用有针对性和无偏见的方法来确定决定B细胞淋巴瘤对公认的遗传毒性化疗药物的反应的基因和遗传途径。首先，我们将重点研究促凋亡介质的BH3家族，以检验这些蛋白在肿瘤发生和化疗反应中的相对作用。随后，我们将使用RNAi筛选方法来检测数千个癌症相关基因在化疗反应中的作用。最后，我们将针对已建立的肿瘤生存途径来确定当被灭活时，使化疗耐药淋巴瘤对传统化疗药物敏感的基因。我们希望我们的研究能够确定最终决定某一化疗药物成败的关键节点和途径。

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.