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ROLE OF MIDKINE IN MOLECULAR TARGETED THERAPY TO TIP1 FOR LUNG CANCER TREATMENT

Midkine 在 TIP1 肺癌分子靶向治疗中的作用

基本信息

批准号：
10428615
负责人：
Vaishali Kapoor
金额：
$ 15.32万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-07 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10428615
关键词：
Antibodies Antibody Therapy Apoptosis Attenuated Binding Biological Biological Assay Blocking Antibodies Cancer Biology Cancer Model Cancer Patient Cause of Death Cell Death Cell Proliferation Cell physiology Cell surface Chemotaxis Clinical Treatment Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Data Data Set Development Diagnosis Disease-Free Survival Ensure Epitopes Event Exhibits Flow Cytometry Future Genomic approach Goals Heparin Binding Growth Factor Human Immunofluorescence Immunologic Immunoprecipitation In Vitro Investigation K22 Award Knock-out Knowledge Learning Libraries Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediator of activation protein Modeling Molecular Molecular Chaperones Molecular Target Mus Non-Small-Cell Lung Carcinoma Normal Cell Normal tissue morphology Outcome Pathway interactions Patients Play Pre-Clinical Model Prognosis Prognostic Marker Proteins Proteomics Reporter Research Research Personnel Research Training Rodent Role Scaffolding Protein Signal Transduction Survival Rate Taxes Techniques Testing The Cancer Genome Atlas Therapeutic Tissue Microarray Training Treatment Efficacy Tumor Tissue Up-Regulation WNT Signaling Pathway Xenograft procedure angiogenesis anti-cancer therapeutic base beta catenin cancer cell cancer therapy carcinogenesis chromatin immunoprecipitation cytotoxic cytotoxicity drug development efficacy evaluation evidence base improved in vivo inhibitor innovation knock-down lung cancer cell midkine molecular targeted therapies mortality mouse model novel novel strategies novel therapeutic intervention novel therapeutics overexpression pre-clinical protein expression rho rhotekin skills small molecule inhibitor success targeted treatment tax Gene Products transcriptome sequencing treatment strategy tumor tumor growth

项目摘要

PROJECT DESCRIPTION/ ABSTRACT Non-small cell lung cancer (NSCLC) ranks among the highest cancer-related mortalities world-wide. Molecular targeted therapy is a growing topic of investigation to improve therapeutic efficacy for NSCLC. A few targeted therapies that exploit aberrant protein expression profiles have been approved for NSCLC. However, the marginal percentage of cancers with improved efficacy observed with these therapeutic approaches highlights the need for discovery of additional molecular targets. The proposed research is significant as it will generate new molecular targets and treatment strategies for NSCLC therapy. We propose targeting of the scaffold protein TIP1 that is a novel target for lung cancer as identified by analysis of the cancer genome atlas datasets and NSCLC tumor tissue microarrays. The functional domain of TIP1 (PDZ domain) caps the C-terminus of many different cellular proteins that regulate important cellular functions. Knocking down TIP1 revealed that it plays an important role in cell signaling, cancer development, and progression making it an attractive target for anticancer therapeutics. Comparing antibodies targeting different epitopes of TIP1, it was found that antibodies against the PDZ domain of TIP1 were most effective in inducing direct cytotoxicity of lung cancer cells but not normal cells. Anti-PDZ/TIP1 antibodies injected into mice bearing lung cancer bind specifically to cancer cells and substantially enhance tumor control. Quantitative mass spectrometry identified Midkine (MDK) as a putative protein that modulates this cytotoxicity by anti-PDZ/TIP1 antibodies. Additional studies suggested that the β-catenin/Wnt signaling may be involved in this up-regulation of MDK after blocking of TIP1. Together, these studies led to the central hypothesis that MDK is upregulated by the anti-PDZ/TIP1 antibody via the β- catenin/Wnt signaling pathway, which subsequently modulates downstream cell death mechanisms. Aim 1 will elucidate the mechanisms of induction of MDK following blockade of the PDZ domain of TIP1. This aim will lead to identification of novel molecular targets for NSCLC treatment that have never been considered before. Aim 2 will evaluate the efficacy of blocking TIP1 function while simultaneously blocking MDK function in mouse models of NSCLC. This aim will guide the development of combination therapies to optimize efficacy of NSCLC treatment. This research is innovative because we are studying a novel molecular target, TIP1. Blocking the functional domain of TIP1 leads to NSCLC cell death. We also propose an innovative strategy of dual targeting TIP1 and MDK to enhance the therapeutic efficacy of NSCLC. Building on my cancer biology background, this K22 award will allow me to train in cutting edge proteomic and genomic approaches with special emphasis on identifying novel NSCLC molecular targets. I have proposed a research and training plan that will equip me with the highest skills to ensure my success as an independent investigator. Overall, the long-term goal of my future research, is to provide new opportunities for the development of novel therapies to treat lung cancer.

项目说明/摘要非小细胞肺癌(NSCLC)是世界上癌症相关死亡率最高的疾病之一。分子靶向治疗是提高非小细胞肺癌治疗效果的一个日益重要的研究课题。一些有针对性的利用异常蛋白表达谱的治疗方法已被批准用于非小细胞肺癌。然而，通过这些治疗方法观察到的疗效改善的癌症的边际百分比突出发现更多分子靶标的必要性。拟议的研究具有重要意义，因为它将产生非小细胞肺癌治疗的新分子靶点和治疗策略。我们建议将目标对准脚手架通过对癌症基因组图谱数据集的分析确定TIP1蛋白是肺癌的新靶点和非小细胞肺癌肿瘤组织芯片。TIP1的功能结构域(PDZ结构域)覆盖了C端许多不同的细胞蛋白质调节重要的细胞功能。推倒TIP1揭示了它在细胞信号、癌症发展和进展中发挥重要作用，使其成为有吸引力的靶点抗癌疗法。比较针对TIP1不同表位的抗体发现，抗体针对TIP1的PDZ结构域，TIP1诱导肺癌细胞的直接细胞毒作用最有效，而不是正常细胞。肺癌小鼠体内注射的抗PDZ/TIP1抗体与癌细胞特异性结合并大大加强了对肿瘤的控制。定量质谱仪鉴定中期因子(MDK)为通过抗PDZ/TIP1抗体调节这种细胞毒性的推定蛋白。更多的研究表明 β-catenin/Wnt信号通路可能参与了阻断TIP1后mdk的上调。一起，这些研究导致了一个中心假设，即mdk是由抗pDZ/TIP1抗体通过β-1上调的。连环蛋白/Wnt信号通路，它随后调节下游的细胞死亡机制。目标1将阐明阻断TIP1的PDZ结构域后诱导MDK的机制。这一目标将导致识别用于非小细胞肺癌治疗的新分子靶点，这些靶点以前从未考虑过。目的2评价阻断TIP1功能的同时阻断MDK功能的效果 NSCLC的模型。这一目标将指导联合治疗的发展，以优化疗效非小细胞肺癌治疗。这项研究具有创新性，因为我们正在研究一种新的分子靶标TIP1。阻断TIP1的功能结构域可导致NSCLC细胞死亡。我们还提出了一项创新战略， TIP1和MDK双靶向治疗非小细胞肺癌以我的癌症生物学为基础背景，这个K22奖项将允许我在尖端蛋白质组和基因组学方法方面进行培训特别强调识别新的非小细胞肺癌分子靶标。我提出了一项研究和培训计划这将使我具备最高的技能，以确保我作为一名独立调查员取得成功。总体而言，我未来研究的长期目标是为新疗法的发展提供新的机会用来治疗肺癌。