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（由申请人提供）：自噬对于癌症的发生、进展和治疗反应非常重要，尽管我们已经在临床上尝试针对自噬，但目前还没有办法确定哪些肿瘤会或不会受益于自噬抑制。目前尚不清楚由不同致癌驱动突变驱动的肿瘤是否会 由于不同的肿瘤驱动因素对自噬有相反的影响（例如，突变的 RAS 被认为促进自噬，而 PTEN 的缺失会激活典型的 PIK3C 通路，从而抑制自噬），因此不同的肿瘤可能具有不同的自噬抑制作用。驱动因素的自噬依赖性不同，因此在使用传统（尽管是最先进的）基因工程小鼠（GEM）模型的动物模型中，对自噬抑制的反应不同。有证据表明，RAS 驱动的肿瘤受益于自噬抑制，然而，制造此类 GEM 所需的时间和成本使得对多种临床相关肿瘤驱动因素以及多种自噬调节剂进行直接测试变得非常困难和昂贵。 一种新方法将使我们能够通过针对不同的自噬调节因子以及五种不同的临床相关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效果，并在体外和体内癌症发生和进展过程中进行评估。通过利用 Cramer 实验室首创的一种新方法来实现这一目标，该方法使用与泌尿生殖间充质重组的工程纯化前列腺干细胞来生长模仿正常前列腺组织或由特定肿瘤驱动因素驱动的侵袭性肿瘤的组织重组体（RAS 激活、PTEN 丢失等）我们将把这种新方法与 Thorburn 实验室的新方法结合起来，以靶向和评估自噬，从而使我们能够测试抑制控制自噬过程中不同步骤的三种重要自噬调节因子的效果。由五种不同的肿瘤驱动因素组合驱动的肿瘤细胞均与侵袭性人类前列腺癌相关，并预计对自噬具有不同的、有时相反的影响。我们将进行体外和体内分析来检验我们的中心假设：不同的肿瘤驱动因素导致肿瘤。单元格显示不同度 我们将在体外研究自噬依赖性并响应体内自噬抑制，其目的有两个：1. 确定特定肿瘤驱动的致癌突变对体外自噬和自噬依赖性的影响；2. 确定自噬的作用。在不同致癌突变/驱动因素的背景下，前列腺肿瘤的体内发展和进展这一高风险/高回报项目将确定我们的方法是否可行，从而使我们知道如何进行。我们正在开展一项更大的研究项目，以确定这些效应的重要性和机制，并评估肿瘤突变分析是否可用于选择最有可能对自噬抑制治疗产生反应的癌症患者。我们相信这些特征具有高风险但具有高潜力。能够根据获得的结果确定明确的前进方向，使该项目成为 R21 机制的理想选择。