Regulation of tumor released exosomes and glutamatergic signaling

肿瘤释放的外泌体和谷氨酸信号传导的调节

• 批准号: 8813433
• 负责人: Suzie Chen
• 金额: $ 20.23万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-17 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8813433
• 关键词: Address; Affect; Aftercare; Angiogenic Factor; Antibodies; Apoptosis; Archives; BAY 54-9085; Biopsy; Biopsy Specimen; Blood specimen; Cell Line; Cell Proliferation; Cell membrane; Chemopreventive Agent; Clinical; Clinical Trials; Communication; Cutaneous Melanoma; Data; Dependence; Development; Disease Progression; Ectopic Expression; Enrollment; Event; Family; Future; G-Protein-Coupled Receptors; GRM1 gene; Genetic; Glutamates; Goals; Growth; Human; Immunotherapy; In Vitro; Incidence; Knowledge; Laboratories; Ligands; MAP Kinase Gene; Malignant Neoplasms; Measures; Mediating; Melanoma Cell; Membrane; Modeling; Morbidity - disease rate; Mus; Mutation; Neoplasm Metastasis; Neurons; Oncogenes; Operative Surgical Procedures; PI3K/AKT; Pathogenesis; Pathway interactions; Patients; Phase; Play; Prevention; Process; Production; Property; RNA Interference; Regulation; Reporting; Research Personnel; Riluzole; Role; Sampling; Signal Transduction; Staging; Stem cells; Surrogate Markers; System; Toxic effect; Transgenic Mice; Translating; Up-Regulation; Vesicle; Work; Xenograft procedure; angiogenesis; autocrine; bench to bedside; bone; cell growth; cell transformation; cell type; combinatorial; design; experience; extracellular; gain of function; glutamatergic signaling; human disease; in vivo; melanocyte; melanoma; member; metabotropic glutamate receptor type 1; metastatic process; mortality; mouse model; neoplastic cell; novel strategies; outcome forecast; paracrine; peripheral blood; pre-clinical; public health relevance; receptor; response; success; targeted treatment; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): The incidence of cutaneous melanoma is going up faster than almost any other tumor type in the US and remains one of the most challenging malignancies to treat. Surgical intervention prior to the onset of metastatic spread is a key facto for reducing mortality and morbidity in patients with melanoma, yet, metastases still occur in many patients, resulting in a rather poor prognosis. While there has been some recent success in the development of targeted therapies such as vemurafenib in melanomas that carry the BRAFV600E mutation, the response to these therapies appears transient and treatment is complicated by the development of secondary tumors. Modern immunotherapies such as anti-CTLA-4 or anti-PD1 antibodies have also shown promise with 20%-30% response rates, modest increases in overall survival, and a generally favorable toxicity profile. However, the majority of patients with advance melanoma do not derive lasting benefit from these therapies and new approaches are still needed. Our group demonstrated the etiological role of ectopic expression of a murine neuronal receptor, metabotropic glutamate receptor 1 (GRM1) in mouse melanocytes in genetically modified transgenic mouse models. Aberrant expression of the human form of GRM1 was also observed in H95% of human melanoma cell lines and H65% of biopsy samples but is not expressed by normal human melanocytes, suggesting it is involved in melanomagenesis. Our team has extensive experience and a track record working together in translating results from the bench to the clinic and in the current application our goal is to characterize the mechanisms by which microvesicle (exosomes) are produced in GRM1-expressing melanoma cells and how this contributes to melanoma metastasis. The "Melanoma exosomal messenger system" was first proposed by Hood and colleagues in 2009 as one of the ways melanoma cells communicate within the local tumor microenvironment to enhance tumor cell dissemination. In this application, we will use both genetic and pharmacological approaches to assess the dependence of melanoma cells on active GRM1 and its ligand, glutamate, to produce exosomes. We will also use archived pre-and post-treatment clinical samples from three different trials that incorporated riluzole, a negative modulator of glutamate signaling, to search for a possible correlation between exosome production and biologic response in patients with melanoma. The final Aim will examine riluzole as a chemopreventive agent using our spontaneous metastasis melanoma mouse model that mimics human disease and permits analysis of both early and late stages of metastasis. Our main goal is to unravel the mechanisms responsible for exosome formation in melanoma and to determine what role exosomes play in melanoma progression in order to inform the design of future clinical trials.

 描述（由申请人提供）：皮肤黑色素瘤的发病率在美国几乎比任何其他肿瘤类型上升得更快，并且仍然是治疗最具挑战性的恶性肿瘤之一。在转移性扩散开始之前进行手术干预是降低黑色素瘤患者死亡率和发病率的关键因素，然而，许多患者仍然发生转移，导致预后相当差。虽然最近在开发靶向治疗方面取得了一些成功，例如在携带BRAFV 600 E突变的黑色素瘤中的vemurafenib，但对这些治疗的反应似乎是短暂的，并且继发性肿瘤的发展使治疗变得复杂。现代免疫疗法如抗CTLA-4或抗PD 1抗体也显示出20%-30%的应答率、总体生存期的适度增加和总体有利的毒性特征。然而，大多数晚期黑色素瘤患者并没有从这些治疗中获得持久的益处，仍然需要新的方法。我们的小组证明了在转基因小鼠模型中，小鼠黑素细胞中的鼠神经元受体，代谢型谷氨酸受体1（GRM 1）的异位表达的病因作用。在H95%的人黑素瘤细胞系和H65%的活检样品中也观察到人类形式的GRM 1的异常表达，但在正常人黑素细胞中不表达，这表明它参与了黑素瘤的发生。我们的团队在将结果从实验室转化为临床方面具有丰富的经验和良好的合作记录，在当前的应用中，我们的目标是表征微泡（外泌体）在表达GRM 1的黑色素瘤细胞中产生的机制以及这如何有助于黑色素瘤转移。“黑色素瘤外泌体信使系统”由Hood及其同事于2009年首次提出，作为黑色素瘤细胞在局部肿瘤微环境内通讯以增强肿瘤细胞传播的方式之一。在本申请中，我们将使用遗传和药理学方法来评估黑色素瘤细胞对活性GRM 1及其配体谷氨酸的依赖性，以产生外泌体。我们还将使用来自三个不同试验的存档治疗前和治疗后临床样本，这些试验包括利鲁唑（谷氨酸信号的负调节剂），以寻找黑色素瘤患者外泌体产生和生物反应之间可能的相关性。最终的目标将使用我们的自发转移黑色素瘤小鼠模型来检查利鲁唑作为化学预防剂，该模型模拟人类疾病并允许分析早期和晚期转移。我们的主要目标是解开黑色素瘤中外泌体形成的机制，并确定外泌体在黑色素瘤进展中发挥的作用，以便为未来临床试验的设计提供信息。