microRNA as biomarkers for the response to immunotherapy in melanoma

microRNA 作为黑色素瘤免疫治疗反应的生物标志物

• 批准号: 8383931
• 负责人: QING-SHENG MI
• 金额: $ 15.93万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8383931
• 关键词: Binding; Biological Assay; Biological Markers; Cell physiology; Cells; Clinical Trials; Cytotoxic T-Lymphocyte-Associated Protein 4; Development; Early Diagnosis; FDA approved; Figs - dietary; Formalin; Functional RNA; Gene Expression; Human; Immune; Immunotherapeutic agent; Immunotherapy; Individual; Intervention; Malignant Neoplasms; Mediating; Metastatic Melanoma; MicroRNAs; Molecular Profiling; Neoplasm Metastasis; Outcome; Paraffin Embedding; Patients; Peripheral; Radiation therapy; Recombinants; Relative (related person); Reporting; Resistance; Serum; Side; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Transcript; Tumor Tissue; Unresectable; cancer type; chemotherapy; conventional therapy; design; human monoclonal antibodies; melanoma; neoplastic cell; outcome forecast; response; therapeutic target; therapy resistant; tumor

DESCRIPTION (provided by applicant): Malignant melanoma (MM) is one of the most invasive human cancers with its relative resistance to conventional chemotherapy and radiotherapy; only a small percentage of patients demonstrated durable responses to immunotherapy. Thus, a personalized strategy is urgently needed to develop assays which may guide the individual patient in the selection of appropriate therapy. Discovery of predictive biomarkers for immunotherapy response is an important strategy to attain this objective, which is stated in "Provocative Questions" for this RFA. MicroRNAs (miRNA) are small non-coding RNAs which regulate gene expression. Altered miRNA expression in tumor cells are found in variety types of cancer and contribute to therapy resistance in some cancer. We recently found that miRNAs are involved in immune cell development and function, and that cell-free serum from MM patients contains MM-specific miRNAs, which may serve as biomarkers for MM early diagnosis and prognosis. This application is designed to test the hypothesis that different miRNA expression profiles can be detected, either in MM tumor or in therapeutic targeting T cells, between patients who are responsive and who are resistant to immunotherapy. These differences could be reflected in the serum, which can potentially serve as convenient, noninvasive biomarkers for prediction of response to immunotherapy. We will begin by identifying the tumor-specific (Aim 1) and T cell-specific (Aim 2) miRNA expression profiles between therapy-responsive and therapy-resistant patients using TaqMan TR-PCR arrays; then will define serum specific miRNAs. The results from the proposed pioneering studies may enable us to predict MM patients who will respond to immunotherapy, using tissue/serum miRNAs as biomarkers, and may also facilitate the development of new intervention strategies for increasing immunotherapy for MM. PUBLIC HEALTH RELEVANCE: Malignant melanoma (MM) is one of the most invasive human cancers with high potential for metastasis. The management of MM has been challenging due to its relative resistance to conventional therapy and immunotherapy. Discovery of predictive biomarkers for immunotherapy response is an important strategy to guide the individual patient in the selection of appropriate therapy, which is stated in "Provocative Questions" of this RFA. MicroRNAs (miRNA), small non-coding RNAs which regulate gene expressions, are involved in cancer development. This application is designed to identify specific miRNAs in MM tumor, therapeutic targeting T cells, and the serum as biomarkers for prediction of response to immunotherapy. The results from the proposed studies may enable us to predict MM patients who will respond to immunotherapy, and may also facilitate the development of new intervention strategies for increasing immunotherapy for MM.

描述(申请人提供)：恶性黑色素瘤(MM)是最具侵袭性的人类癌症之一，它对传统的化疗和放射治疗相对耐药；只有一小部分患者对免疫治疗有持久的反应。因此，迫切需要一种个性化的策略来开发可以指导个体患者选择适当治疗的分析方法。发现免疫治疗反应的预测生物标记物是实现这一目标的重要战略，这在本RFA的“挑衅性问题”中有陈述。MicroRNAs(MiRNA)是一种调节基因表达的非编码小RNA。肿瘤细胞中miRNA表达的改变在各种类型的癌症中都被发现，并在一些癌症中导致治疗抵抗。我们最近发现miRNAs参与了免疫细胞的发育和功能，而MM患者的无细胞血清中含有MM特异性的miRNAs，这些miRNAs可以作为MM早期诊断和预后的生物标志物。这一应用旨在测试一种假设，即在MM肿瘤中或在治疗靶向T细胞中，在对免疫治疗有反应和耐药的患者之间可以检测到不同的miRNA表达谱。这些差异可以反映在血清中，它们可能成为预测免疫治疗反应的方便、非侵入性的生物标志物。我们将首先使用TaqMan tr-PCR阵列识别治疗反应患者和耐药患者之间的肿瘤特异性(Aim 1)和T细胞特异性(Aim 2)miRNA表达谱；然后将定义血清特异性miRNAs。拟议的开创性研究的结果可能使我们能够使用组织/血清miRNAs作为生物标记物来预测多发性骨髓瘤患者对免疫治疗的反应，也可能有助于开发新的干预策略来增加多发性骨髓瘤的免疫治疗。 公共卫生相关性：恶性黑色素瘤(MM)是最具侵袭性的人类癌症之一，具有很高的转移潜力。多发性骨髓瘤的治疗一直具有挑战性，因为它对传统疗法和免疫疗法具有相对抵抗力。发现免疫治疗反应的预测生物标记物是指导个体患者选择适当治疗的重要策略，这在本RFA的“挑衅性问题”中有陈述。MicroRNAs(MiRNA)是一种调节基因表达的非编码小RNA，参与癌症的发展。这一应用旨在确定MM肿瘤中特定的miRNAs、治疗性靶向T细胞和血清作为预测免疫治疗反应的生物标志物。拟议的研究结果可能使我们能够预测MM患者对免疫治疗的反应，也可能有助于开发新的干预策略，以增加MM的免疫治疗。