Translational application of mouse models of melanoma brain metastases

黑色素瘤脑转移小鼠模型的转化应用

基本信息

批准号：
10371885
负责人：
Suzie Chen
金额：
--
依托单位：
VA NEW JERSEY HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-10-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10371885
关键词：
Allografting Amyotrophic Lateral Sclerosis Animal Model Animals Apoptosis Appearance Archives Automobile Driving Basic Science Biological Models Biopsy Blood Blood - brain barrier anatomy Brain Cancer Patient Cell Cycle Arrest Cell Line Cell Transplantation Cells Characteristics Clinic Clinical Clinical Trials Colorectal Cancer Critical Pathways Cysteine DNA Damage Deterioration Development Disease Ectopic Expression Enrollment Etiology Experimental Models FDA approved Family General Population Genotype Glutamate Receptor Glutamates Homeostasis Human Immune Immune Evasion Immune checkpoint inhibitor Immune response Immunocompetent Immunological Models Immunotherapy In Vitro Interruption Investigational Therapies Laboratory Finding Lesion Ligands Link Longitudinal Studies Luciferases Lung MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Mediating Melanoma Cell Metastatic Melanoma Metastatic malignant neoplasm to brain Modeling Modification Monitor Mus Mutate Mutation NRAS gene Neoplasm Metastasis Neoplasms Neuraxis Neurologic Neurons Operative Surgical Procedures Organ PI3K/AKT Paraffin Pathway interactions Patients Pharmacotherapy Population Positioning Attribute Primary Neoplasm Prognosis Property Quality of life Radiation Radiation therapy Reactive Oxygen Species Reduced Glutathione Relapse Resistance Riluzole Sampling Signal Pathway Signal Transduction Site Solid Neoplasm Suggestion Technology Therapeutic Toxic effect Transgenic Mice Transgenic Model Transgenic Organisms Translating Translational Research Translations Work Xenograft procedure anticancer research base cancer therapy chemotherapeutic agent combinatorial cytokine design glutamatergic signaling human model humanized mouse improved improved outcome in vivo inhibitor innovation malignant breast neoplasm melanocyte melanoma metabotropic glutamate receptor type 1 military veteran molecular pathology mouse model multidisciplinary neoantigens neoplastic cell non-invasive monitor novel strategies patient response peripheral blood pre-clinical preclinical study prevent progression marker reconstitution response response biomarker small molecule targeted treatment therapeutically effective tool translational applications translational model treatment response tumor tumor microenvironment tumor progression

Allografting Amyotrophic Lateral Sclerosis Animal Model Animals Apoptosis Appearance Archives Automobile Driving Basic Science Biological Models Biopsy Blood Blood - brain barrier anatomy Brain Cancer Patient Cell Cycle Arrest Cell Line Cell Transplantation Cells Characteristics Clinic Clinical Clinical Trials Colorectal Cancer Critical Pathways Cysteine DNA Damage Deterioration Development Disease Ectopic Expression Enrollment Etiology Experimental Models FDA approved Family General Population Genotype Glutamate Receptor Glutamates Homeostasis Human Immune Immune Evasion Immune checkpoint inhibitor Immune response Immunocompetent Immunological Models Immunotherapy In Vitro Interruption Investigational Therapies Laboratory Finding Lesion Ligands Link Longitudinal Studies Luciferases Lung MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Mediating Melanoma Cell Metastatic Melanoma Metastatic malignant neoplasm to brain Modeling Modification Monitor Mus Mutate Mutation NRAS gene Neoplasm Metastasis Neoplasms Neuraxis Neurologic Neurons Operative Surgical Procedures Organ PI3K/AKT Paraffin Pathway interactions Patients Pharmacotherapy Population Positioning Attribute Primary Neoplasm Prognosis Property Quality of life Radiation Radiation therapy Reactive Oxygen Species Reduced Glutathione Relapse Resistance Riluzole Sampling Signal Pathway Signal Transduction Site Solid Neoplasm Suggestion Technology Therapeutic Toxic effect Transgenic Mice Transgenic Model Transgenic Organisms Translating Translational Research Translations Work Xenograft procedure anticancer research base cancer therapy chemotherapeutic agent combinatorial cytokine design glutamatergic signaling human model humanized mouse improved improved outcome in vivo inhibitor innovation malignant breast neoplasm melanocyte melanoma metabotropic glutamate receptor type 1 military veteran molecular pathology mouse model multidisciplinary neoantigens neoplastic cell non-invasive monitor novel strategies patient response peripheral blood pre-clinical preclinical study prevent progression marker reconstitution response response biomarker small molecule targeted treatment therapeutically effective tool translational applications translational model treatment response tumor tumor microenvironment tumor progression

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项目摘要

Much has been learned about the molecular pathology of melanoma in recent years and significant progress has been made towards its treatment, yet late-stage melanoma still remains one of the least curable cancers with high metastatic propensity. The brain is a common site of metastasis for patients with various neoplasia including melanoma, breast cancer, lung cancer, and colorectal cancer. The mainstay for treatment of brain metastasis has been radiation therapy; sometimes surgery and chemotherapeutic agents have been included. Most clinical trials usually excluded patients with brain metastases because of the unlikelihood these patients will benefit from such regiment, however, recently a few trials have included melanoma patients with or without brain metastases. Preliminary results from these trials are suggestive that similar responsiveness was observed for patients with or without brain metastases, and further trials are needed to confirm these results. Despite these improvements, patients with multiple brain metastases from solid tumors often show progression in the brain contributing to neurological deterioration, decreased quality of life, and poor survival. Mouse models reflecting human cancers are important tools towards the translation of basic science discoveries to clinical therapies. However, rapidly evolving technologies within the last few years require further refining current approaches that enable models to be more suitable in robust translational applications to provide consistent information to meet patients’ needs. In our studies of melanoma, we discovered that >65% of human melanoma cell lines and melanoma biopsies express metabotropic glutamate receptor 1 (GRM1), independent of N-RAS/B-RAF genotypes, while normal human melanocytes do not. Based on this discovery, our group was the first to propose the link between GRM1-mediated glutamatergic signaling and melanoma. In recent clinical trials, we observed that >90% of all enrolled patients expressed GRM1 within their late-stage melanomas. However, the conventional mouse models of melanoma do not mimic this genetic alteration common to melanoma patients. Therefore, we developed mouse models (MASS and TGS) where the ectopic expression of GRM1 in previously normal melanocytes leads to consistent, wide-spread development of melanocytic lesions and metastasis to various organs including the lung and brain, two common metastatic sites for human melanoma. In this application, we propose to characterize the ability of these two different but complementary innovative models that mimic human melanoma with brain metastases and fill the gap, to expand, improve, and transform the utility of mammalian tumor models for translational research. Completion of this proposed work is an essential step towards establishing fundamentally important and relevant animal models of human cancer that will improve and save cancer patient lives.

近年来，关于黑色素瘤的分子病理已经了解了很多东西，并且取得了重大进展已经对其治疗进行了，但后期黑色素瘤仍然是最不可治愈的癌症之一具有高转移性的承诺。大脑是各种肿瘤患者的转移的常见部位包括黑色素瘤，乳腺癌，肺癌和大肠癌。治疗大脑的主要支柱转移一直是放射治疗；有时包括手术和化学治疗剂。大多数临床试验通常排除脑转移患者，因为这些患者的不可能是但是，将从该团中受益，但是最近，一些试验包括有或没有的黑色素瘤患者脑转移。这些试验的初步结果表明观察到相似的响应能力对于有或没有脑转移的患者，需要进一步的试验来确认这些结果。尽管如此改进，实体瘤的多个脑转移患者通常显示出大脑的进展有助于神经系统定义，生活质量降低和生存差。反映人类癌的鼠标模型是转化基础科学发现的重要工具进行临床疗法。但是，在过去几年内快速发展的技术需要进一步精炼当前的方法使模型能够更适合强大的翻译应用程序提供一致的信息以满足患者的需求。在我们的黑色素瘤研究中，我们发现人类> 65％黑色素瘤细胞系和黑色素瘤活检表达代谢性谷氨酸受体1（GRM1），独立 N-RAS/B-RAF基因型的，而正常的人类黑色素细胞则没有。基于这一发现，我们的小组是第一个提出GRM1介导的谷氨酸能信号传导与黑色素瘤之间的联系。在最近的临床上试验，我们观察到，所有入学的患者中有90％在其后期黑色素瘤中表达了GRM1。然而，传统的黑色素瘤小鼠模型并不模仿这种遗传改变黑色素瘤患者。因此，我们开发了小鼠模型（质量和TG），其中的异位表达以前正常黑素细胞中的GRM1导致黑素细胞病变的一致，广泛的发育和转移到包括肺和大脑在内的各种器官，人类的两个常见转移部位黑色素瘤。在此应用程序中，我们建议表征这两个不同但完整的能力创新模型与脑转移模仿人黑色素瘤并填补空白，扩大，改善和转换哺乳动物肿瘤模型的效用以进行转化研究。这项拟议工作的完成是建立根本重要和相关的人类癌症模型的重要一步这将改善并挽救癌症患者的生命。