Metabolomic and miRNA profiling of vitreous humor in uveal melanoma

葡萄膜黑色素瘤玻璃体液的代谢组学和 miRNA 分析

• 批准号: 10029073
• 负责人: F. Yesim Demirci
• 金额: $ 41.53万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10029073
• 关键词: Accounting; Adjuvant Therapy; Adult; Affect; Behavior; Biological; Biological Markers; Biology; Biopsy; Biopsy Specimen; Brachytherapy; Categories; Cessation of life; Choroid; Ciliary Body; Classification; Clinical; Clinical Trials; Cutaneous; Data; Diagnosis; Disease; Environment; Epigenetic Process; Evaluation; Eye; Eye Color; Fine needle aspiration biopsy; Future; Gene Expression Profiling; Goals; Immune response; Intervention; Iris; Knowledge; Light; Liquid substance; Liver; Malignant Neoplasms; Medical Genetics; Metabolic; Metabolic Pathway; MicroRNAs; Molecular; Molecular Genetics; Neoplasm Metastasis; Pathway interactions; Patients; Population; Posterior eyeball segment structure; Primary Neoplasm; Procedures; Resources; Risk; Role; Sampling; Site; Skin; Testing; Tissues; Uvea; Uveal Melanoma; Vitreous humor; base; biomarker development; candidate marker; clinical care; clinical predictors; differential expression; effective therapy; eye preservation; improved; in silico; liquid chromatography mass spectrometry; melanocyte; melanoma; metabolic profile; metabolomics; mortality; new therapeutic target; next generation sequencing; novel therapeutics; outcome forecast; potential biomarker; prognostic; prognostic assays; small molecule; therapeutic target; tool; trend; tumor; tumor behavior

PROJECT SUMMARY / ABSTRACT The uveal tract (iris, ciliary body, and choroid) of the eye contains melanocytes and can develop melanoma. Although overall rare, accounting for about 5% of all melanomas, uveal melanoma (UM) represents the most common primary intraocular cancer observed in adult population. UM is a highly aggressive cancer with a strong propensity to metastasize, often to the liver. Currently, there is no effective therapy for metastatic UM, which leads to death in less than a year in most cases. Ongoing clinical trials, however, provide some hope with promising results for adjuvant therapy and better management of metastatic disease; hence effective prognostication and optimal surveillance remain essential. A commercial prognostic test currently available for UM involves gene expression profiling (GEP) of primary tumor samples, often obtained by fine-needle aspiration biopsy prior to commonly used eye-preserving brachytherapy. GEP identifies two major prognostic categories (class 1 with low and class 2 with high metastatic risk); however, patients with class 1 tumors may still develop metastases. Moreover, because of well-known tumor biopsy-related issues/concerns, there remains a need for a more accurate and tumor biopsy-free (biofluid-based) prognostic testing in primary UM. Given that UM predominantly involves the choroid at posterior eye segment (~90%), the vitreous humor that fills the posterior eye cavity, constitutes an excellent candidate for biofluid-based UM biomarker development. Unlike the systemic fluids, which can be affected by multiple factors/conditions, the vitreous' composition predominantly reflects/mirrors local eye environment. Cancer has the hallmarks of metabolomic and epigenetic reprogramming and, in recent years, cancer-associated metabolic and epigenetic perturbations have emerged as new potential biomarkers and therapeutic targets. To our knowledge, UM-related metabolomics studies are lacking and vitreous miRNA studies are very limited. Considering the feasibility and potential clinical utility of small molecule (metabolite and miRNA) profiling of biofluids, we propose to comprehensively examine the vitreous metabolites and miRNAs in UM patients in order to investigate the potential utility of vitreous profiling to distinguish different UM prognostic subtypes and utilize our findings to (i) advance our understanding of molecular perturbations underlying the UM biology, (ii) unravel new potential biomarkers for future UM prognostication improvement efforts, and (iii) uncover new therapeutic targets for future clinical interventions. Our preliminary metabolomics data provide support for potential utility of vitreous profiling to distinguish between UM subtypes and also implicate some new intriguing biological pathways/mechanisms. Hence, the results of our study are expected to advance our knowledge of UM and serve as an essential first step towards improving the UM diagnosis, prognostication, and management.

项目概要/摘要 眼睛的葡萄膜（虹膜、睫状体和脉络膜）含有黑色素细胞，可形成黑色素瘤。 虽然总体上比较罕见，约占所有黑色素瘤的 5%，但葡萄膜黑色素瘤 (UM) 代表了最常见的黑色素瘤。 在成年人中观察到的常见原发性眼内癌。 UM 是一种高度侵袭性的癌症， 强烈的转移倾向，通常转移至肝脏。目前，尚无针对转移性 UM 的有效治疗方法， 在大多数情况下，这会导致不到一年的死亡。然而，正在进行的临床试验给我们带来了一些希望 辅助治疗和更好地管理转移性疾病的有希望的结果；因此有效 预测和最佳监测仍然至关重要。目前可用于商业预测测试 UM 涉及原发肿瘤样本的基因表达谱 (GEP)，通常通过细针获得 在常用的保眼近距离放射治疗之前进行抽吸活检。 GEP 确定了两个主要的预测 类别（低转移风险的 1 类和高转移风险的 2 类）；然而，患有 1 类肿瘤的患者可能 仍会发生转移。此外，由于众所周知的肿瘤活检相关问题/担忧， 原发性 UM 仍然需要更准确且无需肿瘤活检（基于生物流体）的预后测试。 鉴于 UM 主要累及眼后段的脉络膜 (~90%)，玻璃体液充满 眼后腔，是基于生物流体的 UM 生物标志物开发的绝佳候选者。 与受多种因素/条件影响的全身液体不同，玻璃体的成分 主要反映/镜像局部眼睛环境。癌症具有代谢组学和表观遗传的特征 重编程以及近年来与癌症相关的代谢和表观遗传扰动已经出现 作为新的潜在生物标志物和治疗靶点。据我们所知，与密歇根大学相关的代谢组学研究 缺乏且玻璃体 miRNA 研究非常有限。考虑到可行性和潜在的临床效用 生物体液的小分子（代谢物和 miRNA）分析，我们建议全面检查 UM 患者的玻璃体代谢物和 miRNA，以研究玻璃体分析的潜在效用 区分不同的 UM 预后亚型，并利用我们的发现来 (i) 增进我们对 UM 生物学基础的分子扰动，(ii) 揭示未来 UM 的新的潜在生物标志物 预测改善工作，以及（iii）发现未来临床干预的新治疗目标。 我们的初步代谢组学数据为玻璃体分析的潜在效用提供了支持，以区分 UM 亚型之间的差异，还涉及一些新的有趣的生物途径/机制。因此， 我们的研究结果预计将增进我们对 UM 的了解，并作为迈向 UM 的重要第一步 改善 UM 诊断、预测和管理。