TURNing RanBP9 on NSCLC

将 RanBP9 应用于非小细胞肺癌

基本信息

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
项目类别：
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

项目摘要

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.

项目概要非小细胞肺的治疗最近取得了显着进展癌症（非小细胞肺癌）。靶向治疗和免疫治疗使患者病情得到显着缓解仅在 5 年前，这种疾病是不可想象的，它是癌症相关死亡的第一大原因。发达国家。不幸的是，大多数患者没有获得持久的反应并且没有被治愈。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。 RanBP9 保护 NSCLC 细胞来自 DNA 损伤剂（例如铂类药物）引起的压力。其水平越高，情况越差 NSCLC 患者对铂类药物的反应。该支架蛋白显着过度表达与正常细胞相比，在 NSCLC 细胞中，这是基于其抗应激保护功能。因此，治疗窗口可能会针对 RanBP9 打开而不损害正常细胞。另一方面，与许多其他癌症治疗的潜在靶点一样，RanBP9 广泛表达。 RanBP9 在大脑和性腺中表达相对较高，例子。因此，在将灭活RanBP9的想法付诸临床之前，需要进行仔细的工作这样做是为了更好地了解 RanBP9 如何保护细胞免受 DNA 损伤。除了癌细胞之外，尤其重要的是确定这种蛋白质如何在肿瘤相关巨噬细胞（TAM）中发挥作用，已被证明可促进肿瘤发生和对治疗的耐药性。为了实现这些目标，整个有机体建模是必要的。该提案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治疗时，RanBP9 在正常细胞和癌细胞中均出现。为了区分相互作用癌细胞中的 RanBP9 来自其余肿瘤微环境中的癌细胞，我们将使用新的小鼠系称为 RanBP9-TURN，其中在 Cre 所在的细胞中 RanBP9-HA 关闭，RanBP9-V5 打开积极的。在本提案的第一个具体目标（目标 1）中，我们将研究 RanBP9 在 II 型中的相互作用 RanBP9 标签从 HA 切换为小鼠模型中的肺细胞和肺泡巨噬细胞 Cre 重组后的 V5。这将确定治疗后 RanBP9 相互作用组的变化在正常肺泡 II 型细胞和肺泡巨噬细胞中使用顺铂。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 蛋白相互作用的动态。这将揭示顺铂 DNA 损伤后癌细胞和 TAM 中 RanBP9 相互作用组的变化。完成后，这项研究将为追求机械设计的疗法提供支持基于 RanBP9 的靶向治疗 NSCLC。它还将开辟新的调查线来调查未知的情况细胞对 DNA 损伤的反应机制。最后，RanBP9-TURN 将成为原型用于研究肿瘤微环境的小鼠模型领域。