Multiple mutations in tumor maintenance

描述(申请人提供)：项目摘要。这项提议详细说明了一项培训计划，以促进候选人在癌症生物学方面的学术生涯的发展。候选人将利用这段专门的时间来巩固和集中她的独立研究计划。候选人将接受顶尖癌症生物学家哈罗德·瓦默斯博士的指导，他培养了许多多产的科学家。纪念斯隆-凯特琳癌症中心将提供机构支持。将提供充足的资源和多种职业发展活动来帮助应聘者实现她的目标。 长期目标是通过干扰关键的癌基因来彻底根除癌细胞。具体的假设是肿瘤的维持依赖于多个癌基因。其基础是1)多种癌基因突变导致哺乳动物细胞恶性转化，2)肿瘤依赖于启动癌基因的持续表达，并在其失活后退化，3)一些残留细胞对原发癌基因失活具有抵抗力，并与复发有关。研究将集中于Myc和Ras途径癌基因在肿瘤进展和维持中的作用，首先通过使用小鼠乳腺肿瘤模型系统，然后转换到人类细胞系统。具体目标是： 1.建立乳腺癌模型，其中Myc和RAS通路的单个或多个癌基因的表达受多西环素的调节。 2.评估肿瘤对次癌基因单独失活或原癌基因和次癌基因组合失活的反应。 3.确定可能导致对癌基因失活和肿瘤复发的抵抗的致癌突变。 关联性。该提案解决了与人类癌症直接相关的三个问题：1)在给定的肿瘤中发现的所有突变蛋白中，有多少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，哪些是最关键的干扰以根除癌症？3)常见的人类癌基因MYC和RAS的致癌伙伴是什么？

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?