Project 4

项目4

基本信息

批准号：
10434090
负责人：
Eva Hernando
金额：
$ 28.22万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-19 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434090
关键词：
Adjuvant Adjuvant Study Adjuvant Therapy Automobile Driving Biological Biological Assay Biological Markers Biological Sciences Biology CLIA certified CRISPR/Cas technology Cancer Biology Candidate Disease Gene Cell Proliferation Cells Chemicals Clinical Clinical Management Clinical Research Companions Data Diagnosis Disease Disease Progression Effectiveness Excision Formalin Gene Expression Profile Gene Expression Profiling Genes Goals Gold Growth Guide RNA Histologic Human Immune Immune Evasion Immune checkpoint inhibitor Immune response Immunocompetent Immunologic Adjuvants In Vitro International Isogenic transplantation Liquid substance Measures Melanoma Cell Messenger RNA Metastatic Melanoma MicroRNAs Modeling Modification Molecular Molecular Analysis Morbidity - disease rate Mus National Comprehensive Cancer Network Neoplasm Metastasis Operative Surgical Procedures Outcome Pathway interactions Patient risk Patient-Focused Outcomes Patients Pattern Phase Phase III Clinical Trials Placebo Control Placebos Population Primary Neoplasm Probability Prognosis Prognostic Marker Prospective cohort Randomized Recurrence Relapse Resected Risk Role Sampling Scientific Advances and Accomplishments Technology Testing Therapeutic Therapeutic Intervention Thick Time Tissues Toxic effect Tumor Tissue Tumor-Derived Ulcer Validation Xenograft procedure anti-PD-1 arm base biomarker validation checkpoint therapy clinical practice clinically relevant cohort cost effectiveness evaluation experimental study high risk immunosuppressed improved in vivo inhibitor therapy insight melanoma nano-string neoplastic cell new therapeutic target novel pembrolizumab placebo controlled trial predictive modeling prognostic prognostic assays prospective relapse prediction relapse risk sample fixation small molecule inhibitor standard care success survival outcome treatment strategy tumor tumor growth tumor progression validation studies

项目摘要

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.

项目 4 摘要尽管最近的治疗取得了进展，但原发性黑色素瘤患者的预后仍然较差。诊断时临床和组织学相似的黑色素瘤通常具有截然不同的结果：虽然有些在初次手术切除后即可治愈，但另一些则出现局部复发并转移，并最终死亡，这种高度可变的结果表明了潜在的生物学差异。肿瘤（细胞内在）和/或患者本身（宿主、细胞外在，例如分子免疫反应）。在诊断时可以可靠测量的肿瘤变化可能是有用的预后标志物。鉴于其中一些标记物也可能推动疾病进展，他们的研究可能会产生新的见解黑色素瘤生物学并产生新的治疗靶点最近的试验已经证明了佐剂。晚期黑色素瘤（III 期和 IV 期）的治疗可降低黑色素瘤复发和转移率(1-3) 。辅助免疫和小分子抑制剂疗法的成功开启了扩展的可能性它们用于 II 期患者，对于这些患者来说，辅助治疗尚未成为标准治疗的一部分。具有显着的毒性、金钱成本和可能准确的伴随检测的不明确的长期益处。分配患者的复发风险，甚至预测患者从辅助治疗中获益——测量为提高无复发生存率（RFS）——可以改变临床管理、减少不必要的发病率和 MicroRNA (miRNA) 是有前途的生物标志物，因为它们在组织和体液中的稳定性，以及它们在癌症生物学（包括黑色素瘤）中的作用。开发一组候选 miRNA 可以整合到复发预测模型中，该模型可以预测 II 期患者的结果和辅助治疗的益处，以及一些预后 miRNA 我们高度鉴定了基于肿瘤组织的 miRNA 特征。 II 期黑色素瘤患者的预后，并使用独立的患者队列来证明其在识别短（<3 年）与长（>3 年）RFS 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，一种目前临床实验室采用的最先进技术，用于开发 II 期复发预测模型根据肿瘤样本中的 miRNA 表达来识别黑色素瘤患者（目标 1）； miRNA 调节机制（例如细胞增殖、免疫逃避）驱动肿瘤转移扩散来自原发肿瘤的黑色素瘤细胞（目标 2）；以及 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黄金标准（目标 3）。该项目的完成有望展示纳入新颖的复发预测模型的潜力进入 II 期黑色素瘤患者的管理，并揭示有助于的候选基因和途径黑色素瘤的进展并可能成为新的治疗靶点。