Project 4

项目4摘要 尽管最近治疗取得了进展，转移性黑色素瘤的预后仍然很差。原发疾病的患者 临床和组织学相似的黑色素瘤的诊断结果往往大相径庭： 其中一些在初次手术切除后治愈，另一些则出现局部复发(S)和 转移，并最终死亡。这种高度可变的结果表明，在 肿瘤(细胞内的)和/或患者本身(宿主、细胞外的，例如免疫反应)。分子 可以在诊断时可靠测量的肿瘤变化可能是有用的预后标志。此外， 考虑到其中一些标记物也可能推动疾病的进展，他们的研究可能会对 黑色素瘤生物学和产生新的治疗靶点。最近的试验表明，佐剂 晚期黑色素瘤的治疗(III期和IV期)可降低黑色素瘤复发和转移率(1-3) 。 佐剂免疫和小分子抑制剂疗法的成功为扩大治疗提供了可能性。 它们用于II期患者，对他们来说，辅助治疗还不是标准护理的一部分。然而，这些疗法 有显著的毒性、金钱成本和不清楚的长期收益。配套化验可能准确地 分配患者的复发风险，甚至预测患者从辅助治疗中获得的好处-衡量如下 增加无复发生存率(RFS)-可以改变临床管理，减少不必要的发病率和 毒性，并显著改善患者的预后。MicroRNAs(MiRNAs)是很有前途的生物标记物，因为 它们在组织和液体中的稳定性，以及它们在癌症生物学中的已证明作用，包括在黑色素瘤中。我们 假设一组候选miRNA可以集成到复发预测模型中，该模型可以 预测II期患者的结果和辅助治疗的好处，以及一些预后的miRNAs 在功能上调节黑色素瘤的进展。我们鉴定了一种基于肿瘤组织的miRNA签名 II期黑色素瘤患者预后的预测，并使用独立的患者队列来证明 它在识别短(&lt；3年)和长(&gt；3年)RFS患者方面具有出色的判别准确性。 在这里，我们建议通过以下方式改变黑色素瘤的临床实践和研究范式：1)使用纳米串，一种 目前临床实验室采用最先进的技术，为第二阶段开发复发预测模型 基于肿瘤样本中miRNA表达的黑色素瘤患者(目标1)；2)确定临床相关 MiRNA调节的机制(例如，细胞增殖、免疫逃避)，推动转移性传播 来自原发肿瘤的黑色素瘤细胞(目标2)；以及3)检验复发预测模型的临床有效性 在一项随机的前瞻性试验中，生物标志物临床验证的黄金标准(AIM 3)。成功 该项目的完成有望展示纳入新的复发预测模型的潜力 深入到II期黑色素瘤患者的治疗中，并揭示候选基因和途径 可能导致黑色素瘤进展，并可能成为新的治疗靶点。

PROJECT 4 SUMMARY Despite recent therapeutic advances, prognosis for metastatic melanoma remains poor. Patients with primary melanomas that are clinically and histologically similar at diagnosis often have vastly different outcomes: whereas some are cured after initial surgical resection, others develop loco-regional recurrence(s) and metastases, and eventually die. Such highly variable outcomes suggest underlying biological differences in tumors (cell-intrinsic) and/or the patients themselves (host, cell-extrinsic, e.g. immune response). Molecular alterations in tumors that can be robustly measured at diagnosis could be useful prognostic markers. Moreover, given that some of these markers may also drive disease progression, their study may yield novel insights into melanoma biology and generate new therapeutic targets. Recent trials have demonstrated that adjuvant treatments for advanced melanoma (stage III and IV) reduce rates of melanoma recurrence and metastasis(1-3) . The success of adjuvant immune and small molecule inhibitor therapies has opened the possibility of extending their use to stage II patients, for whom adjuvant therapy is yet not part of standard care. However, these therapies have a significant toxicity, monetary cost, and unclear long-term benefit. Companion assays that might accurately assign a patient’s risk of recurrence and even predict a patient’s benefit from adjuvant therapy—measured as increased relapse-free survival (RFS)—could transform clinical management, reduce unnecessary morbidity and toxicity, and dramatically improve patient outcomes. MicroRNAs (miRNAs) are promising biomarkers because of their stability in tissues and fluids, and their demonstrated roles in cancer biology, including in melanoma. We hypothesize that a set of candidate miRNAs can be integrated into a relapse-prediction model that can predict stage II patient outcomes and benefits from adjuvant therapy, and that some prognostic miRNAs functionally modulate melanoma progression. We identified a tumor tissue-based miRNA signature highly prognostic of outcome for stage II melanoma patients and used an independent cohort of patients to demonstrate its excellent discriminatory accuracy for identifying patients with short (<3 years) versus long (>3 years) RFS. Here we propose to transform melanoma clinical practice and research paradigms by: 1) using NanoString, a state-of-the-art technology currently employed in clinical labs, to develop a relapse-prediction model for stage II melanoma patients based on miRNA expression in tumor samples (Aim 1); 2) identifying clinically relevant miRNA-regulated mechanisms (e.g., cell proliferation, immune evasion) that drive metastatic spread of melanoma cells from the primary tumor (Aim 2); and 3) testing the clinical validity of the relapse-prediction model in a randomized, prospective trial, the gold standard for clinical validation of biomarkers (Aim 3). Successful completion of this project promises to demonstrate the potential of incorporating a novel relapse-prediction model into the management of stage II melanoma patients, and reveal candidate genes and pathways that contribute to melanoma progression and might emerge as new therapeutic targets.