Project 4

项目4概要 尽管最近的治疗进展，转移性黑色素瘤的预后仍然很差。原发性 在诊断时临床和组织学上相似的黑色素瘤通常具有非常不同的结果： 而有些在初次手术切除后治愈，另一些发展为局部区域复发， 转移，最终死亡。这种高度可变的结果表明， 肿瘤（细胞内源性）和/或患者自身（宿主、细胞外源性，例如免疫应答）。分子 在诊断时可以可靠地测量的肿瘤中的改变可以是有用的预后标志物。此外，委员会认为， 考虑到这些标志物中的一些也可能驱动疾病进展，他们的研究可能会产生新的见解， 黑色素瘤生物学和产生新的治疗靶点。最近的试验表明， 晚期黑色素瘤（III期和IV期）的治疗降低了黑色素瘤复发和转移的比率（1-3）。 辅助免疫和小分子抑制剂疗法的成功打开了扩展的可能性 它们用于II期患者，对于这些患者，辅助治疗还不是标准治疗的一部分。然而，这些疗法 具有显著的毒性、金钱成本和不明确的长期益处。配套检测可以准确地 分配患者的复发风险，甚至预测患者从辅助治疗中的获益， 增加无复发生存期（RFS）-可以改变临床管理，减少不必要的发病率， 毒性，并显着改善患者的结果。microRNAs（miRNAs）是有前途的生物标志物， 它们在组织和体液中的稳定性，以及它们在癌症生物学中的作用，包括在黑色素瘤中。我们 假设一组候选miRNAs可以整合到复发预测模型中， 预测II期患者的结局和辅助治疗的益处，并且一些预后miRNA 在功能上调节黑色素瘤进展。我们发现了一个基于肿瘤组织的miRNA标签， II期黑色素瘤患者的预后，并使用一个独立的患者队列来证明 它在识别短RFS（<3年）与长RFS（>3年）患者方面具有出色的区分准确性。 在这里，我们建议通过以下方式改变黑色素瘤临床实践和研究范式：1）使用NanoString， 目前在临床实验室采用的最先进的技术，以开发II期复发预测模型 基于肿瘤样品中miRNA表达的黑素瘤患者（目的1）; 2）鉴定临床相关的 miRNA调节机制（例如，细胞增殖，免疫逃避），这些因素会导致 来自原发肿瘤的黑素瘤细胞（目的2）;和3）测试复发预测模型的临床有效性 在一项随机前瞻性试验中，生物标志物临床验证的金标准（目标3）。成功 该项目的完成有望证明纳入一种新的复发预测模型的潜力 II期黑色素瘤患者的管理，并揭示候选基因和途径， 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.