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中取得了显着进步 癌症（NSCLC）。靶向和免疫治疗已导致出色的患者缓解 仅5年前就无法想象这种疾病，这是癌症与癌症相关死亡的第一名 发达国家。不幸的是，大多数患者没有达到持久的反应，也无法治愈。 因此，仍然需要新的治疗靶标和策略来治疗这种毁灭性的目标 恶性。 蛋白质RANBP9可能是治疗NSCLC的有吸引力的靶标。 RANBP9保护NSCLC单元 来自由DNA损伤剂（例如铂基毒品）引起的应力。它的水平越高，越差 NSCLC患者对基于铂的药物的反应。该脚手架蛋白明显过表达 与正常对应物相比，在NSCLC细胞中，这是根据其抗抗 压力保护功能。因此，可以打开一个治疗窗口，而无需损坏目标RANBP9 正常细胞。另一方面，像癌症治疗的许多其他潜在靶标一样，RANBP9是 广泛表达。在大脑和性腺中发现了相对较高的ranbp9表达，因为 例子。因此，在将RANBP9灭活的想法带到诊所之前，需要仔细的工作是 这样做是为了更好地了解RANBP9如何保护细胞免受DNA损伤。除了在癌细胞中，它是 确定该蛋白质在肿瘤相关巨噬细胞（TAM）中的工作尤其重要 已显示可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 用顺铂治疗时，RANBP9在正常和癌细胞中均显示出。区分 来自肿瘤微环境中其余部分的癌细胞中的RANBP9，我们将使用新的小鼠系 称为ranbp9-turn，关闭RANBP9-HA，RANBP9-V5在CRE为CRE的单元格中打开 积极的。 在本提案的第一个特定目的（目标1）中，我们将研究RANBP9在II型中的相互作用 在小鼠模型中，RANBP9标签从HA转换为小鼠模型中的肺细胞和肺泡巨噬细胞中 V5在CRE重组后。这将建立治疗后RANBP9相互抗乳的变化 在正常肺泡II型细胞和肺泡巨噬细胞中伴有顺铂。在第二个目标（AIM 2）中，我们将 研究NSCLC细胞中RANBP9蛋白相互作用的动力学和DNA损伤的TAM。这会 揭示了顺铂DNA损伤后，癌细胞和TAM的RANBP9相互作用变化。 完成后，这项研究将为追求机械设计的疗法提供支持 根据RANBP9的靶向处理NSCLC。它还将为未知的新调查开放 细胞对DNA损伤反应的机制。最后，ranbp9-turn将是 小鼠建模领域，以研究肿瘤微环境。