Autophagy regulation of prostate tumor development

自噬调节前列腺肿瘤的发展

• 批准号: 9096644
• 负责人: Scott D Cramer
• 金额: $ 20.29万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096644
• 关键词: Affect; Animal Model; Antineoplastic Agents; Automobile Driving; Autophagocytosis; Benign; Cell Survival; Cells; Characteristics; Clinic; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Dependence; Dependency; Development; Ductal; Embryo; Engineering; Ensure; Exhibits; Exploratory/Developmental Grant; Genes; Genetic; Genetically Engineered Mouse; Genitourinary system; Grant; Head; Human; In Vitro; Knock-out; Lead; Lesion; Lung; Lysosomes; MAP3K7 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mesenchyme; Methods; Mitotic; Mus; Mutation; Oncogenes; Oncogenic; PTEN gene; Paper; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Process; Prostate; Prostatic Neoplasms; Recombinants; Regulation; Research; Research Project Grants; Role; Stem cells; Structure; TP53 gene; Testing; Time; Tissues; Work; actionable mutation; base; cancer cell; cell growth; clinically relevant; cost; design; high risk; improved; in vivo; inhibition of autophagy; inhibitor/antagonist; knock-down; melanoma; mouse model; mutant; neoplastic cell; new technology; novel strategies; pancreatic neoplasm; public health relevance; research study; response; tumor; tumor growth

 DESCRIPTION (provided by applicant): Autophagy is important in cancer development, progression and response to therapy. Although we are already trying to target autophagy in the clinic, there is currently no way to identify the tumors that will or will not benefit from autophay inhibition and it is unknown if tumors that are driven by different oncogenic driver mutations will differ in their response to autophagy inhibition or not. Because different tumor drivers have opposing effects on autophagy (e.g. mutant RAS is thought to promote autophagy while loss of PTEN activates the canonical PIK3C pathway which should inhibit autophagy), it is likely that tumors with different drivers will differ in their autophagy dependency and thus respond differently to autophagy inhibition. In animal models using conventional (albeit state of the art) genetically engineered mouse (GEM) models, accumulating evidence suggests that RAS-driven tumors benefit from autophagy inhibition. However the time and cost associated with making such GEMs makes testing multiple clinically relevant tumor drivers head to head along with multiple autophagy regulators very difficult and expensive. In this pilot project we aim to develop a new approach that will allow us to directly assess the effects of inhibiting autophagy by targeting different autophagy regulators and in tumor cells driven by five different clinically relevant prostate tumor drivers and to do so both in vitro and during cancer development and progression in vivo. We will do this by capitalizing on a novel approach pioneered by the Cramer lab that uses engineered purified prostate stem cells recombined with urogenital mesenchyme to grow tissue recombinants that mimic normal prostate tissue or aggressive tumors driven by specific tumor drivers (RAS activation, PTEN loss etc.). We will combine this new approach with new methods from the Thorburn lab to target and assess autophagy, allowing us to test the effects of inhibiting three essential autophagy regulators that control distinct steps in the autophagy process in tumor cells driven by five different combinations of tumor drivers all associated with aggressive human prostate cancer and predicted to have different and sometimes opposing effects on autophagy. We will perform both in vitro and in vivo analysis to test our central hypothesis: different tumor drivers cause tumor cells to display different degrees of autophagy dependence in vitro and respond to autophagy inhibition in vivo. We will do this with two aims: 1. Determine the effects of specific tumor-driving oncogenic mutations on autophagy and autophagy-dependence in vitro. And 2. Determine the role of autophagy in prostate tumor development & progression in vivo in the context of different oncogenic mutations/drivers. This high risk/ high return project will establish if our approach is feasible o not and thus allow us to know how to proceed with a larger research project to determine the importance and mechanism of these effects and assess whether analysis of tumor mutations can be used to select patients whose cancer is most likely to respond to autophagy inhibition therapy. We believe these characteristics of high risk but potential for high return with the abiliy to identify a clear way forward based on the results obtained makes this project ideal for the R21 mechanism.

 描述（由应用提供）：自噬在癌症发展，进展和对治疗的反应中很重要。尽管我们已经在试图靶向诊所中的自噬，但目前尚无识别会或不会从自动赛抑制中受益的肿瘤，并且未知是否由不同的致癌驱动器突变驱动 他们对自噬抑制的反应是否不同。由于不同的肿瘤驱动因素对自噬的影响（例如突变的RAS被认为会促进自噬，而PTEN损失会激活规范的PIK3C途径，这应该抑制自噬），因此具有不同驱动因素的肿瘤可能在自噬依赖性方面有所不同，因此对自噬抑制的反应也有所不同。在使用常规（尽管最新的）通用小鼠模型（GEM）模型的动物模型中，积累的证据表明，由RAS驱动的肿瘤受益于自噬抑制作用。但是，与制作此类宝石有关的时间和成本使得测试多个临床相关的肿瘤驱动器与多个自噬调节剂一起头部非常困难和昂贵。在这个试点项目中，我们旨在发展 一种新的方法将使我们能够通过靶向不同的自噬调节剂以及由五个不同临床相关的前列腺肿瘤驱动因素驱动的肿瘤细胞来直接评估抑制自噬的影响，并在体外以及在体内癌症发育和进展过程中这样做。我们将通过利用Cramer Lab开创的新方法来实现这一目标，该方法使用工程化的纯化前列腺干细胞与泌尿生殖器间充质重组以生长模仿正常前列腺组织或由特定肿瘤驱动器驱动的攻击性肿瘤的组织重组（RAS激活，PTEN，PTEN损失等）。我们将将这种新方法与从索伯恩实验室（Thorburn Lab）进行的新方法结合起来，以进行靶向和评估自噬，使我们能够测试抑制三个基本的自噬调节剂的效果，这些调节剂控制着由五种不同组合的肿瘤细胞中自噬过程中的明显步骤，这些肿瘤驱动器组合的肿瘤驱动因素与激进的人类癌症和有时对自动效应的影响不同。我们将同时进行体外和体内分析以测试我们的中心假设：不同的肿瘤驱动器会导致肿瘤细胞显示不同的程度 体外自噬依赖性并响应体内自噬抑制作用。我们将以两个目的来做到这一点：1。确定特定的肿瘤肿瘤突变对体外自噬和自噬依赖性的影响。和2。在不同的致癌突变/驱动因素的情况下，确定自噬在前列腺肿瘤发育和体内进展中的作用。这个高风险/高回报项目将确定我们的方法是否是可行的，因此使我们能够知道如何进行更大的研究项目，以确定这些作用的重要性和机制和评估，并评估肿瘤突变的分析是否可以用于选择对自动噬菌体抑制疗法最有可能反应的癌症的患者。我们认为，这些具有高风险的特征，但可能会根据获得的结果来确定一个明确的前进方向的高回报的潜力，这使得该项目非常适合R21机制。