A microRNA based prognostic service that predicts melanoma metastasis likelihood

基于 microRNA 的预后服务可预测黑色素瘤转移的可能性

• 批准号: 8644238
• 负责人: Isabel Kurth
• 金额: $ 19.97万
• 依托单位: RGENIX, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-11 至 2016-02-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644238
• 关键词: Adjuvant; Apolipoproteins A; Biological Assay; Biological Markers; Biotechnology; Businesses; Cancer Patient; Cessation of life; Clinical; Collaborations; Communities; Data; Data Analyses; Data Set; Decision Making; Diagnosis; Disease; Distal; Economics; Endothelial Cells; Gene Expression Profile; Gene Expression Profiling; Gene Targeting; Genes; Goals; Health Care Costs; Health Personnel; Healthcare; Immunohistochemistry; Immunotherapy; Incidence; Individual; Investigational Therapies; Laboratories; Lead; Legal patent; Licensing; Malignant Neoplasms; Measurement; Melanoma Cell; Memorial Sloan-Kettering Cancer Center; Metastasis Suppressor Genes; Metastatic Melanoma; Methods; MicroRNAs; Molecular; Neoplasm Metastasis; Newly Diagnosed; Organ; Pathologic; Patients; Phase; Predictive Value; Prevention therapy; Primary Neoplasm; Probability; Prognostic Marker; Proteins; Protocols documentation; Recurrence; Relapse; Research; Retrospective Studies; Rights; Risk; Sampling; Sensitivity and Specificity; Services; Slide; Small Business Innovation Research Grant; Societies; Specimen; Stratification; Technology; Testing; Therapeutic; Time; United States; Universities; base; cancer cell; chemotherapy; cohort; experience; high risk; improved; killings; melanoma; metastasis prevention; mortality; novel; outcome forecast; overexpression; phase 2 study; prevent; prognostic; programs; prospective; public health relevance; receptor; tumor

ABSTRACT Melanoma is a highly prevalent cancer that kills patients by metastasizing and destroying distal organs. To date, there are no effective molecular prognostic services available for stratifying patients that are at high risk for metastatic relapse in the adjuvant setting. By stratifying patients into high-risk versus low-risk, therapies could be tailored to those patients that stand to benefit from treatment while sparing those patients who will not relapse and not require costly and potentially harmful therapies. Recent research identified three miRNAs (miR-1908, miR-199a5p, and miR-199a3p) that are overexpressed in metastatic melanoma cells and inhibit expression of apolipoprotein A (ApoE), a metastasis suppressor in melanoma. Cancer-cell secreted ApoE prevents cellular invasion and metastatic endothelial recruitment through engaging melanoma cell LRP1 and endothelial cell LRP8 receptors, respectively. Importantly, elevated expression levels of miRNAs in primary tumor samples performs robustly in stratifying melanoma patients into those with high likelihood from those with very low likelihood for metastatic relapse. Here, Rgenix proposes to develop a prognostic service that predicts the likelihood of melanoma metastasis relapse, based on gene expression analysis of the miRNA/ApoE gene signature in primary tumor slides. The long-term goal is to provide a service that allows all patients diagnosed worldwide with melanoma to be screened and profiled for their risk of developing metastasis. This information will guide clinicians in the critical decision-making for accurate treatment of each patient. To that aim, a protocol for combined expression analysis of the three miRNA by quantitative real-time PCR and ApoE by immunohistochemistry will be developed to stratify patients into those at high versus low risk for metastasis relapse with a >80% positive predictive value. Furthermore, Rgenix will determine the sensitivity and specificity of the assay and establish an optimal threshold for the intensity of each miRNA and ApoE expression that will allow for stratification of high-risk versus low-risk relapsers. A >80% sensitivity and specificity will proof feasibility of the approach and allow proceeding to Phase II. In Phase II the threshold and biomarker combination determined in Phase I will be validated in a large retrospective patient cohort, and improved in order to reach >85% specificity and sensitivity. This threshold will be used to initiate prospective trials in collaboration with Memorial Sloan Kettering Cancer Center. In addition, a CLIA-CAP certified laboratory will be set up and Rgenix will promote the product, and obtain 3rd party reimbursement. Rgenix' prognostic service would prove invaluable for society, which is experiencing increasing incidence of melanoma, and for the clinical community, which is constrained by economic forces to restrict metastasis prevention therapies to patients at highest risk for metastatic relapse.

抽象的 黑色素瘤是一种非常普遍的癌症，它通过转移和破坏远端器官来杀死患者。到 迄今为止，尚无有效的分子预后服务可用于对高危患者进行分层 用于辅助治疗中的转移性复发。通过将患者分为高风险和低风险，治疗 可以针对那些能够从治疗中受益的患者进行量身定制，同时避免那些无法从治疗中受益的患者 复发且不需要昂贵且可能有害的治疗。最近的研究发现了三种 miRNA （miR-1908、miR-199a5p 和 miR-199a3p）在转移性黑色素瘤细胞中过表达并抑制 载脂蛋白 A (ApoE) 的表达，这是黑色素瘤中的一种转移抑制因子。癌细胞分泌的ApoE 通过与黑色素瘤细胞 LRP1 结合来防止细胞侵袭和转移性内皮募集 内皮细胞LRP8受体分别。重要的是，原代细胞中 miRNA 的表达水平升高 肿瘤样本在将黑色素瘤患者分层为高可能性患者方面表现强劲 转移复发的可能性非常低。在这里，Rgenix 提议开发一种预测服务 根据基因表达分析预测黑色素瘤转移复发的可能性 原发性肿瘤载玻片中的 miRNA/ApoE 基因特征。长期目标是提供一种服务，让所有人 全球范围内被诊断患有黑色素瘤的患者将接受筛查并分析其罹患黑色素瘤的风险 转移。这些信息将指导临床医生做出关键决策，以准确治疗每种疾病 病人。为此，我们制定了一种通过实时定量对三种 miRNA 进行组合表达分析的方案 将开发通过免疫组织化学进行的 PCR 和 ApoE，以将患者分为高风险组和低风险组 对于转移复发，阳性预测值>80%。此外，Rgenix 将确定灵敏度 和测定的特异性，并为每个 miRNA 和 ApoE 的强度建立最佳阈值 表达将允许对高风险和低风险复发者进行分层。 >80% 的灵敏度和 特异性将证明该方法的可行性并允许进入第二阶段。在第二阶段，阈值和 第一阶段确定的生物标志物组合将在大型回顾性患者队列中得到验证，并且 改进以达到 >85% 的特异性和敏感性。该阈值将用于启动前瞻性 与纪念斯隆凯特琳癌症中心合作进行的试验。此外，CLIA-CAP 认证实验室 将成立，Rgenix 将推广该产品，并获得第 3 方报销。 Rgenix 的预测 事实证明，服务对于黑色素瘤发病率不断上升的社会来说是无价的，对于 临床界受到经济力量的限制，将转移预防疗法限制在 转移复发风险最高的患者。