Prognostic and Functional Role of microRNAs in Melanoma Brain Metastasis

描述（由申请人提供）：黑色素瘤脑转移（B-Met）预后不佳，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病程中会发生B-Mets。目前还没有有效的治疗方法，到目前为止也没有分子标记物可以预测哪些原发肿瘤最有可能发展为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，并且在原发性黑色素瘤发生时可以检测到b - met特异性miRNA特征。我们假设其中一些mirna在控制黑色素瘤B-Met增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，B-Met相关的mirna将在体内测试其调节黑色素瘤细胞系B-Met潜能的能力。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如何调节转移过程的理解，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。此外，积极参与黑色素瘤B-Met的miRNA和miRNA靶点的鉴定有可能为目前尚无可行方法的患者提供新的治疗途径。在这项研究中，我们还将在一个前瞻性患者队列中评估B-Met miRNA在诊断时的预测能力。作为一种新颖有效的疗法，能够穿透血脑

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'.