Development of a new molecular predictor for risk of distant metastases in melanoma

开发黑色素瘤远处转移风险的新分子预测因子

• 批准号: 10078265
• 负责人: Sheri L Holmen
• 金额: $ 14.26万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078265
• 关键词: AKT inhibition; AKT1 gene; Adjuvant Therapy; BRAF gene; Biological Assay; Biological Markers; Brain; CDKN2A gene; Chemoprevention; Clinic; Clinical; Clinical Management; Data; Data Set; Detection; Development; Disease; Disease Progression; Distant Metastasis; Early Diagnosis; Formalin; Future; Gene Expression; Gene Expression Profile; Genes; Genetically Engineered Mouse; Goals; Growth; Immunotherapy; Incidence; Intervention Studies; Lesion; MAP Kinase Gene; Metastatic Melanoma; Metastatic Neoplasm to the Lung; Metastatic malignant neoplasm to brain; Methods; Molecular; Molecular Profiling; Morbidity - disease rate; Multivariate Analysis; Mus; Mutate; Neoplasm Metastasis; PI3K/AKT; PTEN gene; Paraffin Embedding; Pathologic; Pathway interactions; Patients; Predictive Value; Prevention; Prevention approach; Prevention strategy; Primary Neoplasm; Prognosis; Prospective cohort; Proto-Oncogene Proteins c-akt; Publishing; Recurrence; Resistance; Resistance development; Resources; Retrospective Studies; Risk; Sampling; Sensitivity and Specificity; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Tissue Embedding; Translating; Treatment Failure; Tumor Suppressor Proteins; Up-Regulation; Validation; assay development; base; cancer type; clinically relevant; cohort; effective therapy; fight against; high risk; improved; melanoma; mortality; mouse model; mutational status; novel; novel therapeutics; predictive marker; prevent; prognostic; prognostic assays; prospective; risk stratification; screening; standard of care; success; surveillance strategy; targeted treatment; therapy resistant; translational impact; treatment group; treatment site

New therapies have significantly improved the management of melanoma but brain metastases continue to be a major component of treatment failure. The ability to identify those patients who are at highest risk of developing brain metastases is very challenging with current methods. Successful development of sensitive and specific prognostic methods for prediction of brain metastases risk in earlier stage melanoma patients would enable the development of more effective surveillance strategies and prospective trials for chemoprevention of brain metastasis development in these high-risk patients. Gene expression signatures have been shown to be prognostic in multiple cancer types and prior gene expression profiles (GEP) of metastases have been published for melanoma. However, the sensitivity and specificity as well as the positive and negative predictive value of these assays remains suboptimal and no specific molecular signature has been described for predicting risk of brain metastases. We analyzed multiple independent gene expression datasets and identified a list of genes that robustly predicts the development of brain metastases. To translate this finding to the clinic, we will optimize the most robust genes in formalin-fixed paraffin embedded tissue and integrate the findings with other relevant biomarkers of disease progression. Recent analysis of metastatic lesions from melanoma patients revealed that brain metastases had significantly higher levels of active phosphorylated AKT (pAKT) than extracranial metastases. We validated these findings by expressing activated AKT in our established melanoma mouse model and observed lung and brain metastases in ~80% of the mice. Based on these data, we hypothesize that the combination of an optimized gene expression signature along with other relevant clinical and pathologic variables, will identify those melanoma patients at highest risk for the development of brain metastases. We will use our rich resource of patient samples to test our hypothesis. While therapeutic intervention to prevent brain metastases in melanoma is our long-term goal, in order for this to be implemented most effectively it is crucial that we develop more accurate methods to identify those patients at highest risk for the development of metastatic disease before those metastases occur. The objective of this study is to generate a clinical/molecular predictor for risk of brain metastases in melanoma patients and to validate the sensitivity and specificity of an optimized clinical/molecular prognostic assay for the development of brain metastases in a retrospective study of Stage II/III melanoma patients. With the recent approval of adjuvant therapies that include stage III disease, we have an enormous opportunity to intervene when there is minimal or non-detectable disease and not only prevent melanoma recurrence but also improve overall survival. As these adjuvant therapies are not without risk, successful completion of the aims in this project will have significant translational impact by identifying those patients that are most likely to benefit from adjuvant therapy.

新疗法显着改善了黑色素瘤的治疗，但脑转移仍然存在 治疗失败的一个重要组成部分。能够识别那些患病风险最高的患者 对于目前的方法来说，脑转移是非常具有挑战性的。成功开发敏感和特异性 预测早期黑色素瘤患者脑转移风险的预后方法将使 制定更有效的脑部化学预防监测策略和前瞻性试验 这些高风险患者的转移发展。基因表达特征已被证明是 多种癌症类型的预后和转移灶的既往基因表达谱 (GEP) 已发表 对于黑色素瘤。然而，敏感性和特异性以及阳性和阴性预测值 这些测定仍然不是最理想的，并且没有描述用于预测风险的特定分子特征 脑转移。我们分析了多个独立的基因表达数据集并确定了一系列基因 强有力地预测脑转移的发展。为了将这一发现转化为临床，我们将优化 福尔马林固定石蜡包埋组织中最强大的基因，并将研究结果与其他相关 疾病进展的生物标志物。最近对黑色素瘤患者转移性病变的分析表明 脑转移瘤的活性磷酸化 AKT (pAKT) 水平显着高于颅外转移瘤 转移。我们通过在我们建立的黑色素瘤小鼠中表达激活的 AKT 来验证这些发现 模型并在约 80% 的小鼠中观察到肺和脑转移。根据这些数据，我们假设 优化的基因表达特征与其他相关的临床和病理学的结合 变量，将识别出那些发生脑转移风险最高的黑色素瘤患者。我们将 使用我们丰富的患者样本资源来检验我们的假设。在治疗干预的同时预防大脑 黑色素瘤转移是我们的长期目标，为了最有效地实施这一目标至关重要 我们开发更准确的方法来识别那些患有最高风险的患者 转移发生之前的转移性疾病。本研究的目的是产生临床/分子 黑色素瘤患者脑转移风险的预测因子，并验证其敏感性和特异性 回顾性研究中针对脑转移发展的优化临床/分子预后测定 II/III 期黑色素瘤患者。随着最近批准了包括 III 期疾病在内的辅助疗法， 当疾病很小或无法检测到时，我们有巨大的机会进行干预，而不仅仅是 预防黑色素瘤复发，同时提高总体生存率。由于这些辅助疗法并非没有风险， 通过确定这些目标，成功完成该项目的目标将产生重大的转化影响 最有可能从辅助治疗中受益的患者。