TURNing RanBP9 on NSCLC

将 RanBP9 应用于非小细胞肺癌

• 批准号: 10198422
• 负责人: Vincenzo Coppola
• 金额: $ 7.8万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198422
• 关键词: 1-Phosphatidylinositol 3-Kinase; Aftercare; Alveolar; Alveolar Macrophages; Animal Model; Attention; Automobile Driving; Binding; Binding Proteins; Biochemical; Brain; C-terminal; Cancer Etiology; Cells; Cellular Stress; Cessation of life; Cisplatin; Clinic; Complex; Cre-LoxP; Cytotoxic agent; DNA Damage; DNA Repair; Data; Disease; Disease remission; Drug usage; Elements; Engineering; Epitopes; Future; Genetic Recombination; Goals; Gonadal structure; Immunoglobulin Switch Recombination; Immunotherapy; Investigation; Link; Literature; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Microtus; Modeling; Mus; Names; Non-Small-Cell Lung Carcinoma; Normal Cell; Normal tissue morphology; Oncogenes; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Platinum; Play; Population; Problem Solving; Protein Dynamics; Proteins; Proteomics; Ras/Raf; Resistance development; Rest; Role; Scaffolding Protein; Solid; Stress; Structure; Testing; Therapeutic; Transforming Growth Factor beta; Tumor Promotion; Tumor-associated macrophages; Tumor-infiltrating immune cells; WNT Signaling Pathway; Whole Organism; Work; alveolar type II cell; base; cBioPortal; cancer cell; cell type; clinically relevant; human disease; human model; in vivo; innovation; interest; lung cancer cell; macrophage; member; mouse model; new therapeutic target; overexpression; patient response; protein degradation; prototype; response; targeted cancer therapy; targeted treatment; therapy design; therapy resistant; tool; treatment strategy; tumor; tumor DNA; tumor microenvironment; tumorigenesis; ubiquitin-protein ligase

Project Summary Remarkable advancements have been recently achieved in the treatment of Non-Small Cell Lung Cancer (NSCLC). Targeted- and immune-therapy have produced spectacular patient remissions unimaginable only 5 years ago for this disease that is the number one cause of cancer related deaths in the developed world. Unfortunately, most patients do not achieve a durable response and are not cured. Therefore, there is still an urgent need for new therapeutic targets and strategies to treat this devastating malignancy. The protein RanBP9 could be an attractive target for the treatment of NSCLC. RanBP9 protects NSCLC cells from stress induced by DNA damaging agents such as platinum based-drugs. The higher its levels, the worse the NSCLC patient response to platinum-based drugs. This scaffold protein is significantly over-expressed in NSCLC cells when compared to the normal counterpart, which is expected on the basis of its anti- stress protective functions. Thus, a therapeutic window might be open to target RanBP9 without damaging normal cells. On the other hand, like numerous other potential targets for cancer therapy, RanBP9 is widely expressed. Relatively high expression of RanBP9 is found in the brain and in the gonads, for example. Therefore, before taking the idea of inactivating RanBP9 to the clinics, careful work needs to be done to better understand how RanBP9 protects cells from DNA damage. Other than in cancer cells, it is particularly important to establish how this proteins works also in tumor associated macrophages (TAMs), which have been shown to promote tumorigenesis and resistance to therapy. To achieve these goals, whole organism modeling is necessary. This proposal seeks to study by advanced proteomics the changes of the molecular interactions that RanBP9 shows in both normal and cancer cells when treated with cisplatin. To distinguish the interactions of RanBP9 in cancer cells from those in the rest of the tumor microenvironment, we will use a new mouse line called RanBP9-TURN in which RanBP9-HA is turned off and RanBP9-V5 is turned on in cells where Cre is active. In the first specific aim (Aim 1) of this proposal, we will study the interactions of RanBP9 in type II pneumocytes and in alveolar macrophages in a mouse model in which RanBP9 tag is switched from HA to V5 upon Cre-recombination. This will establish the changes of the RanBP9-interactome following treatment with cisplatin in normal alveolar type II cells and alveolar macrophages. In the second aim (Aim 2), we will study the dynamics of RanBP9 protein interactions in NSCLC cells and TAMs upon DNA damage. This will reveal the RanBP9-interactome changes in cancer cells and TAMs following DNA damage by cisplatin. When accomplished, this study will add support to the pursue of mechanistically-designed therapies to treat NSCLC based on the targeting of RanBP9. It will also open new lines of investigation into unknown mechanisms of the cellular response to DNA damage. Finally, the RanBP9-TURN will be a prototype in the field of mouse modeling for investigations into the tumor microenvironment.

项目摘要 最近在非小细胞肺的治疗方面取得了显着进展 癌症（NSCLC）。靶向治疗和免疫治疗已经使患者获得了惊人的缓解 仅仅在5年前，这种疾病是不可想象的，它是癌症相关死亡的头号原因， 发达国家。不幸的是，大多数患者没有达到持久的反应，也没有治愈。 因此，仍然迫切需要新的治疗靶点和策略来治疗这种毁灭性的疾病。 恶性肿瘤 RanBP9蛋白可能是治疗NSCLC的一个有吸引力的靶点。RanBP 9保护NSCLC细胞 由DNA损伤剂如铂类药物引起的压力。它的水平越高， NSCLC患者对铂类药物的反应。这种支架蛋白在细胞中显著过表达 在NSCLC细胞中，当与正常对应物相比时，这是基于其抗- 强调保护功能。因此，治疗窗口可能对靶向RanBP 9开放，而不损伤 正常细胞另一方面，像许多其他潜在的癌症治疗靶点一样，RanBP 9是一个潜在的靶点。 广泛表达。RanBP9在脑和性腺中的表达相对较高， example.因此，在将RanBP9灭活的想法应用于临床之前，需要进行仔细的工作， 为了更好地了解RanBP 9如何保护细胞免受DNA损伤。除了癌细胞， 特别重要的是要确定这种蛋白质如何在肿瘤相关巨噬细胞（TAM）中起作用， 其已显示促进肿瘤发生和对治疗的抗性。为了实现这些目标， 整个生物体建模是必要的。 该建议旨在通过先进的蛋白质组学研究分子相互作用的变化， 当用顺铂处理时，RanBP9在正常细胞和癌细胞中均显示。为了区分 RanBP9在癌细胞中与那些在肿瘤微环境中的其余部分不同，我们将使用一种新的小鼠品系 称为RanBP9-TURN，其中RanBP9-HA被关闭，而RanBP9-V5在Cre被激活的细胞中被打开。 活跃 在本提案的第一个具体目标（目标1）中，我们将研究RanBP 9在II型中的相互作用。 在小鼠模型中，RanBP9标签从HA转换为 V5，Cre重组。这将确定治疗后RanBP 9相互作用物组的变化 顺铂在正常肺泡II型细胞和肺泡巨噬细胞中的作用。在第二个目标（目标2）中，我们将 研究DNA损伤后NSCLC细胞和TAM中RanBP9蛋白相互作用的动力学。这将 揭示了顺铂造成DNA损伤后癌细胞和TAM中RanBP9相互作用体的变化。 完成后，这项研究将增加对机械设计疗法的支持， 基于RanBP 9的靶向治疗NSCLC。它还将开辟新的调查路线， 细胞对DNA损伤的反应机制。最后，RanBP9-TURN将成为 研究肿瘤微环境的小鼠模型领域。