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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：
10620161
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/10620161
关键词：
Allografting Amyotrophic Lateral Sclerosis Animal Model Animals Apoptosis Appearance Archives Automobile Driving Basic Science Biological Models Biopsy Blood Brain Cancer Patient Cell Cycle Arrest Cell Line Cell Transplantation Cells Central Nervous System Characteristics Clinic Clinical Clinical Trials Colorectal Cancer Critical Pathways Cysteine DNA Damage Deterioration Development Disease Ectopic Expression Etiology Exclusion Experimental Models FDA approved Family GRM1 gene General Population Genes 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 Learning 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 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 Technology Therapeutic Toxic effect Transgenic Mice Transgenic Model Translating Translational Research Translations Work Xenograft procedure anticancer research blood-brain barrier crossing cancer therapy chemotherapeutic agent combinatorial cytokine design efficacy evaluation glutamatergic signaling human model humanized mouse immune reconstitution 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 participant enrollment patient response peripheral blood pre-clinical preclinical study prevent progression marker response response biomarker small molecule targeted treatment therapeutically effective tool translational applications translational model treatment response tumor tumor microenvironment tumor progression

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，人们对黑色素瘤的分子病理学有了很多了解，并取得了重大进展已经采取了治疗措施，但晚期黑色素瘤仍然是最难治愈的癌症之一具有高转移倾向。脑部是各种肿瘤患者常见的转移部位包括黑色素瘤、乳腺癌、肺癌和结直肠癌。治疗脑部疾病的中流砥柱转移已接受放射治疗；有时包括手术和化疗药物。大多数临床试验通常排除脑转移患者，因为这些患者不太可能将从这样的治疗方案中受益，然而，最近的一些试验包括患有或不患有黑色素瘤的患者脑转移。这些试验的初步结果表明观察到了类似的反应对于有或没有脑转移的患者，需要进一步的试验来证实这些结果。尽管有这些改善，患有实体瘤多发性脑转移的患者通常会出现脑部进展导致神经系统恶化、生活质量下降和生存率低。反映人类癌症的小鼠模型是转化基础科学发现的重要工具到临床治疗。然而，过去几年快速发展的技术需要进一步完善当前的方法使模型更适合稳健的翻译应用程序，以提供一致的信息以满足患者的需求。在我们对黑色素瘤的研究中，我们发现 > 65% 的人类黑色素瘤细胞系和黑色素瘤活检表达代谢型谷氨酸受体 1 (GRM1)，独立 N-RAS/B-RAF 基因型，而正常人类黑素细胞则不然。基于这一发现，我们小组第一个提出 GRM1 介导的谷氨酸信号传导与黑色素瘤之间的联系。近年来临床试验中，我们观察到 >90% 的入组患者在晚期黑色素瘤中表达 GRM1。然而，传统的黑色素瘤小鼠模型并不能模拟这种常见的基因改变。黑色素瘤患者。因此，我们开发了小鼠模型（MASS 和 TGS），其中异位表达先前正常的黑素细胞中的 GRM1 导致黑素细胞病变持续、广泛的发展以及向各种器官的转移，包括肺和脑，这是人类的两个常见转移部位黑色素瘤。在此应用中，我们建议描述这两种不同但互补的能力模仿具有脑转移的人类黑色素瘤并填补空白的创新模型，以扩大、改善和改变哺乳动物肿瘤模型在转化研究中的用途。完成这项提议的工作是建立根本重要且相关的人类癌症动物模型的重要一步这将改善并挽救癌症患者的生命。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.

DOI：
10.18632/oncotarget.28403
发表时间：
2023-04-10
期刊：
ONCOTARGET
影响因子：
0
作者：
Spencer, Kristen R;Portal, Daniella E;Aisner, Joseph;Stein, Mark N;Malhotra, Jyoti;Shih, Weichung;Chan, Nancy;Silk, Ann W;Ganesan, Shridar;Goodin, Susan;Gounder, Murugesan;Lin, Hongxia;Li, Jiadong;Cerchio, Robert;Marinaro, Christina;Chen, Suzie;Mehnert, Janice M
通讯作者：
Mehnert, Janice M

Participation of xCT in melanoma cell proliferation in vitro and tumorigenesis in vivo.