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Characterization of MET alteration using glioblastoma patient-derived xenograft models

使用胶质母细胞瘤患者来源的异种移植模型表征 MET 改变

基本信息

批准号：
10445056
负责人：
Qian Xie
金额：
$ 7.14万
依托单位：
EAST TENNESSEE 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：
2021-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10445056
关键词：
ATM Signaling Pathway Alkylating Agents Automobile Driving Biological Biological Markers Biology Bypass Cell Line Cell Maintenance Cells Clinic Clinical Clinical Trials Combined Modality Therapy Cytogenetics DNA Damage DNA Double Strand Break DNA Repair DNA Repair Inhibition DNA Repair Pathway FDA approved Future Genetic Genomics Glial Fibrillary Acidic Protein Glioblastoma Glioma Gliomagenesis Goals Human In Vitro Incidence MET Oncogene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Modeling Molecular Molecular Target Mutation Pathway interactions Patients Phenotype Property RNA Splicing Radiation Reagent Receptor Protein-Tyrosine Kinases Recurrence Resistance Resources Role Signal Transduction Small Interfering RNA T-Lymphocyte TP53 gene Testing Therapeutic Transgenic Mice Treatment Efficacy Tumor Cell Invasion Tyrosine Kinase Inhibitor Work Xenograft Model autocrine bevacizumab chemotherapy chimeric antigen receptor T cells clinically relevant clinically significant genomic data improved in vivo in vivo Model inhibitor inhibitor therapy interest irradiation mouse model neoplastic cell nestin protein novel overexpression patient derived xenograft model refractory cancer response response biomarker stem cell model stem cells targeted agent targeted treatment therapeutic target therapeutically effective therapy design tool treatment response tumor tumor growth

项目摘要

Project Summary Glioblastoma (GBM) is the most malignant type of brain cancer resistant to alkylating agents and radiation. Glioma stem cells (GSCs), a subpopulation of highly invasive GBM cells resistant to the irradiation and chemotherapy, are the major targets of effective therapeutics. Identifying and targeting molecular determinants of GSCs are important for treating malignant GBM. Our long-term goal is to define and deploy well-characterized, clinically relevant MET-driven GBM models to enable effective therapeutic targeting of MET. Aberrant MET receptor tyrosine kinase (RTK) activation, such as MET amplification (METamp), mutation, and PTPRZ1-MET (ZM) fusion, are frequently found in primary or secondary GBM. Elevated MET signaling provokes tumor invasion in GBM and is also responsible for GSC maintenance and invasive repopulation. Clinically, bevacizumab treatment inducing MET activation is a major mechanism of tumor recurrence with more aggressive phenotype, further demonstrating the significance of targeting MET pathway in GBM. Although MET tyrosine kinase inhibitors (TKIs) are entering clinical trials, their therapeutic efficacy remains controversial. Furthermore, MET inhibitor therapy alone can be defeated by acquired resistance. Therefore, it is important to use clinically relevant GBM models to study the molecular mechanisms in association to therapeutic response to improve the combination strategy. In this application, we hypothesize that GBM PDX models bearing different genetic MET alterations manifest distinct therapeutic vulnerability to MET-targeting agents as well as mechanisms of escape from MET TKIs. We are particularly interested in METamp and ZM fusion models as both molecular features indicate sensitivity to MET inhibitors. For this application, we will 1) Characterize the GBM PDX models bearing various MET alterations found in patients for their MET pathway activation and orthotopic tumor growth. 2) Determine the therapeutic response to MET inhibitors using GSCs in vitro and orthotopic xenograft models in vivo. For MET-targeting reagents we will apply MET TKIs and specific-MET targeting chimeric antigen receptor (CAR) T cells developed at our lab. We will also determine whether irradiation or DNA repair inhibition may enhance the therapeutic efficacy of MET TKIs in these models, and whether MET TKI resistant GBM models may continue respond to MET-targeting CAR T cells. We expect to understand how HGF/MET alteration may serve as biomarkers to indicate the therapeutic response to MET inhibitors as well as the combination strategies. In addition, the GSC models established from this project will become valuable tools for studying MET-mediated GBM biology and therapeutic strategies.

项目摘要胶质母细胞瘤（GBM）是对烷化剂和放射线具有抗性的最恶性的脑癌类型。胶质瘤干细胞（GSC）是一种对辐射具有抗性的高度侵袭性GBM细胞亚群，化疗是有效治疗的主要靶点。识别和靶向分子决定簇对于治疗恶性GBM是重要的。我们的长期目标是定义和部署具有良好特性的，临床相关的MET驱动的GBM模型，以实现MET的有效治疗靶向。异常MET 受体酪氨酸激酶（RTK）激活，如MET扩增（METamp）、突变和PTPRZ 1-MET (ZM)融合，经常发现在原发性或继发性GBM。MET信号升高引起肿瘤侵袭在GBM中，也负责GSC的维持和侵入性再增殖。临床上，贝伐珠单抗诱导MET活化的治疗是具有更侵袭性表型的肿瘤复发的主要机制，进一步证明了靶向MET途径在GBM中的重要性。虽然MET酪氨酸激酶尽管TKI抑制剂（TKI）正在进入临床试验，但其治疗效果仍存在争议。此外，MET 单独的抑制剂疗法可被获得性抗性击败。因此，使用临床相关的 GBM模型，以研究与治疗反应相关的分子机制，以改善治疗反应。组合策略在本申请中，我们假设携带不同遗传MET的GBM PDX模型这些变化表明了对MET靶向药物的明显治疗脆弱性以及逃逸机制从MET TKI。我们对METamp和ZM融合模型特别感兴趣，因为这两种分子特征表明对MET抑制剂敏感。对于此应用，我们将1）表征GBM PDX型号轴承在患者中发现的各种MET改变，用于其MET途径活化和原位肿瘤生长。（二）使用体外GSC和原位异种移植模型确定MET抑制剂的治疗反应， vivo.对于MET靶向试剂，我们将应用MET TKI和特异性MET靶向嵌合抗原受体 (CAR)T细胞在我们的实验室里发展。我们还将确定辐射或DNA修复抑制是否可以增强MET TKI在这些模型中的疗效，以及MET TKI耐药GBM模型是否可以继续对靶向MET的CAR T细胞作出反应。我们希望了解HGF/MET的改变如何作为生物标志物来指示对MET抑制剂的治疗反应以及组合策略。此外，本项目建立的GSC模型将成为研究MET介导的GSC的重要工具。 GBM生物学和治疗策略。