Multiple mutations in tumor maintenance

描述（由申请人提供）：项目摘要。该提案详细介绍了候选人在癌症生物学学术生涯发展的培训计划。候选人将利用这段时间来巩固和集中她的独立研究计划。候选人将由一位领先的癌症生物学家Harold Varmus博士指导，他培养了许多富有成效的科学家。纪念斯隆-凯特琳癌症中心将提供机构支持。充足的资源和多种职业发展活动将可帮助候选人实现她的目标。 长期目标是通过干扰关键的肿瘤致癌基因来实现癌细胞的完全根除。具体的假设是，肿瘤的维持依赖于多种癌基因。它基于以下观察结果：1）多种致癌突变导致哺乳动物细胞的恶性转化，2）肿瘤依赖于起始癌基因的持续表达，并响应于其失活而消退，以及3）许多残留细胞对原发癌基因失活具有抗性，并导致复发。研究将集中在Myc和Ras通路癌基因在肿瘤进展和维持，最初通过使用小鼠乳腺肿瘤模型系统，然后翻译成人类细胞系统。具体目标是： 1.建立乳腺肿瘤模型，其中Myc和Ras途径的单个或多个癌基因的表达受多西环素调节。 2.评价肿瘤对单独的次要癌基因或主要和次要癌基因组合的失活的反应。 3.识别可能导致癌基因失活抵抗和肿瘤复发的致癌突变。 本案无关该提案解决了与人类癌症直接相关的三个问题：1）在给定肿瘤中发现的所有突变蛋白中，有多少蛋白必须被灭活才能根除肿瘤？2)在所有导致肿瘤发生的突变中，为了根除癌症，哪些突变是最关键的？3)什么是共同的人类致癌基因MYC和RAS的致癌伙伴？

DESCRIPTION (provided by applicant): Project Summary. This proposal details a training program for the development of the candidate's academic career in cancer biology. The candidate will use the dedicated period to consolidate and focus her independent research program. The candidate will be mentored by a leading cancer biologist, Dr. Harold Varmus, who has trained numerous productive scientists. The Memorial Sloan-Kettering Cancer Center will provide institutional support. Ample resources and multiple career development activities will be available to help the candidate to achieve her goals. The long-term goal is to achieve complete eradication of cancer cells by interfering with critical tumor oncogenes. The specific hypothesis is that tumor maintenance depends on multiple oncogenes. It is based on the observations that 1) multiple oncogenic mutations contribute to the malignant transformation of mammalian cells, 2) tumors depend on the continuous expression of the initiating oncogene, and regress in response to its inactivation, and 3) a number of residual cells are resistant to primary oncogene inactivation and are responsible for the relapse. Research will focus on Myc and Ras pathway oncogenes in tumor progression and maintenance, initially by using a mouse mammary tumor model system, followed by translation into a human cell system. The specific aims are to: 1. Establish mammary tumor models where the expression of a single or multiple oncogenes of the Myc and Ras pathways is regulated by doxycycline. 2. Evaluate tumor response to the inactivation of a secondary oncogene alone or of a combination of primary and secondary oncogenes. 3. Identify oncogenic mutations that may contribute to the resistance to oncogene inactivation and to tumor relapse. Relevance. The proposal addresses three questions directly relevant to human cancer: 1) Of all the mutant proteins found in a given tumor, how many have to be inactivated in order to eradicate the tumor? 2) Of all the mutations contributing to tumorigenesis, which are the most critical to interfere with in order to eradicate cancer? 3) what are the oncogenic partners of the common human oncogenes MYC and RAS?