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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

基本信息

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
项目类别：
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

项目摘要

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.