The role of autophagy in Kras-driven lung cancer

自噬在 Kras 驱动的肺癌中的作用

• 批准号: 9321425
• 负责人: Yanxiang Guo
• 金额: $ 20.96万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321425
• 关键词: Ablation; Academia; Adenocarcinoma; Anoikis; Antineoplastic Agents; Autophagocytosis; Back; Benign; Biological Sciences; Biology; CRISPR/Cas technology; Cancer Biology; Cancer Institute of New Jersey; Cancer Patient; Carcinoma; Cell Adhesion; Cell Cycle Regulation; Cell Death; Cell Line; Cell Survival; Comprehensive Cancer Center; Cyst; Defect; Doctor of Philosophy; Environment; Funding; Genes; Genetic Engineering; Genetic study; Genus Hippocampus; Goals; Growth; Homeostasis; Human; Hypoxia; Impairment; Institutes; Institution; Instruction; KRAS2 gene; Knock-out; Laboratories; Laboratory Research; Large Cell Carcinoma; Leadership; Lipids; Lung; Lung Neoplasms; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mentors; Metabolic; Metabolic stress; Metabolism; Missense Mutation; Mitochondria; Modeling; Molecular; Molecular Target; Mus; Mutate; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Normal Cell; Normal tissue morphology; Oncogenic; Organelles; Oxyphilic Adenoma; Pathway interactions; Pharmaceutical Preparations; Pre-Clinical Model; Process; Program Development; Protein p53; Protein-Serine-Threonine Kinases; Proteins; Quality Control; RAS inhibition; Regulation; Research; Research Assistant; Research Personnel; Research Training; Role; STK11 gene; Scientist; Site; Somatic Mutation; Squamous cell carcinoma; Starvation; Stress; Survival Rate; TP53 gene; Testing; Tetanus Helper Peptide; Therapeutic; Training; Transgenic Mice; Transition Career Development Award (K22); Tumor Burden; Tumor Suppression; Tumor-Derived; United States National Institutes of Health; Universities; Woman; adenylate kinase; anticancer research; cancer cell; cancer genetics; cancer subtypes; cancer therapy; career; fatty acid oxidation; gain of function; genetic makeup; inhibition of autophagy; innovation; leadership development; meetings; men; metabolomics; mitochondrial autophagy; mortality; mouse model; mutant; mutational status; neoplastic cell; next generation sequencing; novel; novel strategies; novel therapeutic intervention; novel therapeutics; prevent; professor; public health relevance; response; small hairpin RNA; translational approach; tumor; tumor growth; tumor metabolism; tumorigenesis

 DESCRIPTION (provided by applicant): Lung cancer is the most common cancer and has the highest mortality in the US. Tumor metastasis is the major cause of mortality for non-small-cell lung cancer (NSCLC) patients. About 85%-90% of lung cancers are NSCLC and somatic mutations in oncogenic Ras and the tumor suppressor p53 or LKB1 are frequently detected in NSCLC. Unfortunately effective drugs that directly target Ras, p53 or LKB1 have so far not succeeded for cancer therapy. This project investigates the role of autophagy on Kras-driven lung cancer with the ultimate goal of providing a new strategy for lung cancer therapy. Autophagy is a protective process that is activated in response to stress in order to recycle cellular components to maintain homeostasis. During the last five years in the White laboratory, Dr. (Jessie) Yanxiang Guo discovered that cancer cells with Ras activation require autophagy for maintenance of functional mitochondria, for tolerance of metabolic stress and for tumorigenesis. Using two genetic engineered mouse models (GEMMs) for Kras-driven NSCLC with or without p53 and concurrent deletion of essential autophagy gene, autophagy-related-7, Atg7, Dr. Guo found that autophagy deficiency altered the fate of KrasG12D-induced carcinomas to rare, predominantly benign oncocytomas, caused accumulation of defective mitochondria and reduced the tumor growth. With the additional loss of p53, autophagy deficiency impaired mitochondrial fatty acid oxidation (FAO) resulting in defective lipid homeostasis and exquisite sensitivity to metabolic stress. These results suggest that Ras-driven cancers may be susceptible to autophagy inhibition therapy. In this NIH Transition Career Development Award, Dr. Guo, supported by her mentor Dr. Eileen White and her collaborators, plans to test the central hypothesis that autophagy is important for metabolism and growth of lung cancer in the following specific aims: Aim 1 is to determine the extent to which suppression of tumor growth by Atg7 deficiency is reversible and how autophagy inhibition differentially impacts tumor compared to normal tissue; Aim 2 is to determine if autophagy is required to suppress oncocytoma formation and to maintain lipid homeostasis in KrasG12D-driven NSCLC with p53 missense mutations; and Aim 3 is to determine if and how autophagy inhibition impacts Kras-driven lung cancer metastasis. State-of-the-art metabolomic and lipidomic analysis will be used to determine the mechanism by which autophagy regulates cancer metabolism and growth. This project will develop innovative pre-clinical models to determine the role of autophagy in lung cancer and will identify metabolic vulnerabilities created by the altered metabolism. These findings will provide novel translational approaches for Kras-driven lung cancer therapy by dual inhibition of Ras downstream effector pathways and autophagy. Dr, Guo obtained her formalized research training in Dr. Sally Kornbluth 's laboratory at Duke University where she focused on the regulation of cell cycle and cell death in cancer, earning a Ph.D. degree in Molecular Cancer Biology. Currently, Dr. Guo is an Assistant Research Professor in Dr. White's laboratory at Rutgers Cancer Institute of New Jersey (RCINJ) where she has been studying the function of autophagy in regulating Ras-driven cancer metabolism. Dr. Guo's immediate and long-term career goals are to: 1) become a NIH funded independent investigator focusing on metabolism of lung cancer; 2) develop into a leader of a dedicated group of scientists that focus on lung cancer at an NCI-designated comprehensive cancer center or a world-class research university or institute with an excellent scientific environment; and 3) identify new molecular targets for anti-cancer drugs. Dr. Guo will accomplish these goals with three major components: 1) Laboratory research: Dr. Guo will execute her research plan outlined above with full support from Dr. White. She will also receive support and instruction from her collaborators including: Dr. Josh Rabinowitz, a recognized leader in metabolomics at Princeton University, in the use of metabolomics to interrogate cancer metabolism; Dr. Yibing Kang, a recognized leader in cancer metastasis at Princeton University, in novel approaches to interrogate metastasis; Dr. Arnold Levine, a widely acclaimed leader in cancer research and p53 biology at Institute of Advanced Study and RCINJ, to elucidate p53 function and regulation in cancer; Dr. Chan Chang, an expert in the use of Next Generation Sequencing in the study of genetics of cancer at RCINJ; and Dr. Narita at Cancer Research UK, Cambridge Institute, who is generating an inducible Tet-on-shRNA-Atg5 shRNA mouse model that will be provided to Dr. Guo. 2) Didactics: Dr. Guo has and will continue to receive hands-on metabolomics training provided by Dr. Rabinowitz's group. She will take two courses "Introductory XF Training" and "Advanced XT Training" provided by Seahorse Biosciences to study cancer cell metabolism using a Seahorse Bioscience XF Analyzer. She will receive on-site training from Dr. Kang and join his lab meetings to further develop expertise in tumor metastasis. She will also obtain technical advise from Dr. Narita to help successfully generate the Tet-on-shRNA-Atg7 mouse model she proposed. 3) Professional/Leadership Development: Dr. Guo will attend "The objective Analysis of Self and Institution Seminar (OASIS): Leadership and Professional Development Program" offered by Rutgers University for women to help her develop as a leader in academia.

 描述（由适用提供）：肺癌是最常见的癌症，在美国的死亡率最高。肿瘤转移是非小细胞肺癌（NSCLC）患者死亡率的主要原因。大约85％-90％的肺癌是NSCLC，在致癌性RAS中的体细胞突变，NSCLC中经常检测到肿瘤抑制p53或LKB1。不幸的是，直接针对RA，P53或LKB1的有效药物尚未成功接受癌症治疗。该项目调查了自噬在KRAS驱动的肺癌中的作用，其最终目的是为肺癌治疗提供新的策略。自噬是一种受保护的过程，可响应压力而激活，以回收细胞成分以维持稳态。 During the last five years in the White laboratory, Dr. (Jessie) Yanxiang Guo discovered that cancer cells with Ras activation require autophagy for Using two genetic engineered mouse models (GEMMs) for Kras-driven NSCLC with or without p53 and concurrent deletion of essential autophagy gene, autophagy-related-7, Atg7, Dr. Guo found that autophagy deficiency altered the fate of KRASG12D诱导的癌至罕见的，主要是良性的肿瘤瘤，导致线粒体有缺陷的积累并降低肿瘤的生长。随着p53的额外损失，自噬缺陷受损的线粒体脂肪酸氧化（FAO）导致脂质稳态缺陷和对代谢胁迫的独特敏感性。这些结果表明，由RAS驱动的癌症可能容易受到自噬抑制疗法的影响。在NIH过渡职业发展奖中，郭博士在她的心理艾琳·怀特（Eileen White）和她的合作者的支持下，计划测试一个中心假设，即自噬对以下特定目的在以下特定目的中对肺癌的代谢和肺癌的生长很重要：目标1是确定ATG7缺乏症对肿瘤增长的程度，ATG7缺乏症是可逆转和自生的肿瘤抑制作用，使肿瘤具有不同的影响。目的2是确定是否需要自噬来抑制co细细胞瘤形成并维持具有p53错义突变的Krasg12d驱动的NSCLC中的脂质稳态； AIM 3是确定自噬抑制是否影响KRAS驱动的肺癌转移。最先进的代谢组学和脂肪组分析将用于确定自噬调节癌症代谢和生长的机制。该项目将开发创新的临床前模型，以确定自噬在肺癌中的作用，并将确定由改变的代谢产生的代谢脆弱性。发现将通过双重抑制RAS下游效应器途径和自噬来为KRAS驱动的肺癌治疗提供新颖的转化方法。 Guo博士在杜克大学的Sally Kornbluth博士的实验室中获得了正式的研究培训，她专注于对癌症的细胞周期和细胞死亡的调节，获得了博士学位。分子癌生物学学位。目前，Guo博士是新泽西州罗格斯癌症研究所（RCINJ）的怀特博士实验室的助理研究教授，她一直在研究自噬在调节RAS驱动癌症代谢方面的功能。 Guo博士的直接和长期职业目标是：1）成为致力于肺癌代谢的NIH资助的独立研究者； 2）发展成为一群专门的科学家组的领导者，他们专注于NCI指定的综合癌症中心，或具有出色科学环境的世界一流的研究所或研究所； 3）确定抗癌药物的新分子靶标。 Guo博士将通过三个主要组成部分来实现这些目标：1）实验室研究：Guo博士将在White博士的全力支持下执行上面概述的研究计划。她还将获得合作者的支持和指导，包括：乔什·拉比诺维茨（Josh Rabinowitz）博士是普林斯顿大学代谢组学的公认领导者，利用代谢组学来询问癌症代谢；普林斯顿大学癌症转移的公认领导者Yibing Kang博士在质疑转移的新方法中；阿诺德·莱文（Arnold Levine）博士是高级研究和RCINJ研究所广受赞誉的癌症研究和p53生物学领导者，以阐明癌症的p53功能和调节； Chan Chang博士是RCINJ癌症仿制药研究中使用下一代测序的专家；剑桥研究所（Cambridge Institute）的癌症研究所（Cancer Research）的纳里塔（Narita）博士，他正在生成诱导的tet-on-shrna-atg5 shrna小鼠模型，该模型将提供给Guo博士。 2）Didactics：Guo博士已经并且将继续接受Rabinowitz博士小组提供的动手代谢组学培训。她将参加由Seahorse Biosciences提供的两个课程“入门XF培训”和“高级XT培训”，以使用Seahorse Bioscience XF分析仪研究癌细胞代谢。她将接受康博士的现场培训，并参加他的实验室会议，以进一步发展肿瘤转移方面的专业知识。她还将从Narita博士那里获得技术顾问，以帮助成功生成她提出的tet-on-shrna-atg7鼠标模型。 3）专业/领导力发展：郭博士将参加“ Rutgers University for Yousern for Youss Inturance for Academia的领导者，将参加“自我和机构研讨会的客观分析：领导力和专业发展计划”。