Prognostic and Functional Role of microRNAs in Melanoma Brain Metastasis

描述（申请人提供）：黑色素瘤脑转移（B-Met）预后不良，中位生存期不到6个月。不幸的是，大约75%的转移性黑色素瘤患者在其疾病过程中发展为B-Mets。没有有效的治疗方法，到目前为止，还没有分子标记物可以预测哪些原发性肿瘤最有可能进展为B-Met。我们的初步数据强烈支持黑色素瘤B-Met不仅仅是一般侵袭性表型的终末阶段，并且可以在原发性黑色素瘤时检测到B-Met特异性miRNA签名。我们假设这些miRNAs中的一些在控制负责黑色素瘤B-Met的繁殖和建立的分子机制中起关键作用，包括趋化性、粘附、迁移和增殖。首先，将在体内测试B- Met相关miRNA调节黑素瘤细胞系的B-Met潜力的能力。对于筛选中的阳性结果，我们将研究它们可能导致黑色素瘤B-Met的生物学过程和机制。我们的研究结果将极大地促进对miRNA如何调节一般转移过程以及为什么黑色素瘤细胞具有穿透血脑屏障和在神经微环境中增殖的特殊倾向的理解。此外，鉴定积极参与黑色素瘤B-Met的miRNA和miRNA靶点有可能揭示目前没有可行方法的患者的治疗新途径。在这项研究中，我们还将在前瞻性患者队列中评估诊断时B-Met miRNA签名的预测能力。作为一种新型的、有效的疗法， 随着B-met屏障的使用变得可用并且正在辅助环境中进行测试（即维罗非尼），具有预测B-met能力的特征可能对于患者选择变得特别有用。我们应用的成功将满足NCI的目标，即“改善临床风险预测可以帮助临床医生沟通治疗方案的风险/受益概况”。(..)深入了解这种分层的生物学基础将是一个重要的进步，与几种组织的类似病变可能相关。

DESCRIPTION (provided by applicant): Melanoma brain metastasis (B-Met) carries a dismal prognosis, with a median survival of less than 6 months. Unfortunately, approximately 75% of patients with metastatic melanoma develop B-Mets during the course of their disease. There is no effective treatment and thus far there is no molecular marker(s) that can predict which primary tumors are most likely to progress to B-Met. Our preliminary data strongly support that melanoma B-Mets are not merely the terminal stage of a generally aggressive phenotype and that a B-Met-specific miRNA signature can be detected at the time the primary melanoma. We hypothesize that some of these miRNAs play a critical role in governing the molecular mechanisms responsible for the propagation and establishment of melanoma B-Met, including chemotaxis, adhesion, migration, and proliferation. First, B- Met associated miRNAs will be tested in vivo for their ability to modulate B-Met potential of melanoma cell lines. For the positie hits in the screen we will investigate the biological process and mechanism(s) by which they might contribute to melanoma B-Met. The results from our study will greatly advance the understanding of how miRNA modulate the metastatic process in general and why melanoma cells have a particular penchant for penetrating the blood brain barrier and proliferating in the neural microenvironment. Moreover, the identification of miRNAs and miRNA targets that actively participate in melanoma B-Met has the potential to reveal new avenues for treatment in patients for whom no viable approaches are currently available. In this study we will also evaluate the predictive capacity of the B-Met miRNA signature at the time of diagnosis in a prospective patient cohort. As novel, effective therapies with ability to penetrate the blood brain barrier are becoming available and being tested in the adjuvant setting (i.e. vemurafenib), having a signature with ability to predict B-met may become particularly useful for patient selection. Success from our application would satisfy NCI's goals in that 'improved prediction of clinical risk could help clinicians in communicating risk/benefit profiles for treatment options. (..) Insight into the biological basis for this stratification would be an important advance, with likel relevance to analogous lesions of several tissues'.