Stress response networks in cancer: systematic mapping and therapeutic potential

描述（由申请人提供）：癌细胞在极端压力条件下存活和生长，例如氧气和营养供应不足，基因组不稳定和蛋白质组不平衡。我的中心假设是，许多癌细胞适应压力反应途径，并变得独特地依赖于它们。个体应激反应因素已被表征，并且一些目前正在研究作为癌症的药物靶点。然而，我们缺乏对压力反应网络中个体因素的复杂、冗余组织的系统描述。了解这个网络将使我们能够描述癌症特异性适应和脆弱性，这些适应和脆弱性可以用于靶向治疗。为了获得这种深度的洞察力，需要新的系统方法。作为韦斯曼实验室的博士后，我共同开发了一个技术平台，用于系统地绘制哺乳动物细胞中的遗传相互作用。遗传相互作用测量一个突变的表型如何被第二个突变修饰。同时使两个基因失活的强协同效应被称为“合成致死性”。人工合成的致死基因是预防耐药性的有效联合疗法的理想靶点。系统的遗传互作图谱揭示了基因功能和细胞通路.我的长期目标是使用创新的系统方法来了解癌症中压力网络适应的复杂性，并开发其治疗潜力。本申请以多发性骨髓瘤（MM）为例。MM细胞的特征在于应激反应（未折叠蛋白质反应）的组成性激活。尽管最近MM药物治疗取得了进展，但几乎所有患者都会出现耐药性和复发。因此，开发更好的MM联合治疗是一项未满足的临床需求。在我们的MM细胞系平台的初步研究中，我们在应激反应网络中发现了新的遗传脆弱性。这些基因中的几个的表达水平是MM和其他癌症患者的生存预后。本申请的总体目标是确定MM中这些和其他脆弱性之间的相互作用，并验证针对MM和其他癌症中这些协同脆弱性的治疗潜力。我提出了以下具体目标：（1）表征多发性骨髓瘤和其他血液癌细胞中与应激相关的内在脆弱性（2）测试应激相关基因在确定患者细胞中药物敏感性和耐药性中的作用（3）验证靶向多发性骨髓瘤小鼠模型中应激反应网络的治疗潜力。该项目将为在临床试验中测试MM的新组合疗法和生物标志物提供基础，并为我们的遗传相互作用作图方法在各种癌症中的广泛应用铺平道路。通过拟议的研究和培训活动，我将获得必要的技能，开始我作为一个独立的科学家的职业生涯，并奠定了我的研究计划的基础，我计划使用创新的方法来阐明癌症生物学，并确定新的治疗策略，以改善人类健康。

DESCRIPTION (provided by applicant): Cancer cells survive and thrive under extremely stressful conditions, such as inadequate supply of oxygen and nutrients, genomic instability and proteome imbalances. My central hypothesis is that many cancer cells adapt stress response pathways and become uniquely dependent on them. Individual stress response factors have been characterized and some are currently being investigated as drug targets in cancer. However, we lack a systematic description of the complex, redundant organization of individual factors in a stress response net- work. Understanding this network would enable us to characterize cancer-specific adaptations and vulnerabilities that can be exploited for targeted therapies. To gain this depth of insight, new systematic approaches are called for. As a postdoc in the Weissman lab, I have co-developed a technology platform for systematic map- ping of genetic interactions in mammalian cells. Genetic interactions measure how the phenotype of one mutation is modified by a second mutation. A strong synergistic effect of inactivating two genes simultaneously is referred to as "synthetic lethality". Synthetic lethal genes are ideal targets of effective combination therapies that pre-empt drug resistance. Systematic genetic interaction maps reveal gene functions and cellular path- ways. My long-term goal is to use innovative systematic approaches to understand the complexity of stress network adaptations in cancer and exploit their therapeutic potential. This application focuses on multiple myeloma (MM) as a paradigm. MM cells are characterized by constitutive activation of a stress response, the un- folded protein response. Despite recent advances in MM drug therapy, nearly all patients develop resistance and relapse. The development of better combination therapies for MM is thus an unmet clinical need. In preliminary studies with our platform in MM cell lines, we identified novel genetic vulnerabilities in the stress response network. Expression levels of several of these genes are prognostic of survival in MM and other cancer patients. The overall objective of this application is to determine interactions between these and other vulnerabilities in MM, and to validate the therapeutic potential of targeting these synergistic vulnerabilities in MM and other cancers. I propose the following specific aims: (1) Characterize stress-related and intrinsic vulnerabilities in multiple myeloma and other blood cancer cells (2) Test the role of stress-related genes in determining drug sensitivity and resistance in patient cells (3) Validate the therapeutic potential of targeting the stress response network in multiple myeloma mouse models. This project will provide the basis to test new combination therapies and biomarkers for MM in clinical trials, and pave the way for broad application of our genetic interaction mapping approach to a wide variety of cancers. Through the proposed research and training activities, I will acquire the necessary skills to launch my career as an independent scientist, and lay the foundation of my research program, in which I plan to use innovative approaches to elucidate cancer biology and identify new therapeutic strategies to improve human health.