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.

新疗法已大大改善了黑色素瘤的治疗 治疗失败的主要组成部分。识别那些面临发展风险最高的患者的能力 脑转移对当前方法非常具有挑战性。成功发展敏感和特定 预测早期黑色素瘤患者脑转移风险风险的预后方法将使 制定更有效的监视策略和前瞻性试验，以进行大脑化学预防 这些高危患者的转移发展。基因表达特征已显示为 已发表了多种癌症类型和先前基因表达谱（GEP）转移的预后。 用于黑色素瘤。但是，灵敏度和特异性以及正面和负预测值 这些测定仍然是次优的，并且没有描述任何特定的分子特征来预测 脑转移。我们分析了多个独立的基因表达数据集，并确定了一个基因列表 坚固地预测脑转移的发展。为了将此发现转化为诊所，我们将优化 福尔马林固定石蜡嵌入组织中最健壮的基因，并将发现与其他相关的发现结合 疾病进展的生物标志物。最近对来自黑色素瘤患者转移性病变的分析表明， 脑转移的活性磷酸化AKT（PAKT）的水平明显高于颅外 转移。我们通过在我们已建立的黑色素瘤小鼠中表达激活的AKT来验证这些发现 大约80％的小鼠模型并观察到肺和脑转移。基于这些数据，我们假设 优化的基因表达特征以及其他相关临床和病理学的组合 变量将确定那些黑色素瘤患者的脑转移发展风险最高。我们将 使用我们丰富的患者样本资源来检验我们的假设。而治疗干预以防止大脑 黑色素瘤转移是我们的长期目标，为了最有效地实施这一点，这是至关重要的 我们开发了更准确的方法来识别那些患有最高风险的患者的发展 这些转移发生之前的转移性疾病。这项研究的目的是产生临床/分子 预测黑色素瘤患者中脑转移风险的预测指标，并验证 在回顾性研究中，优化的临床/分子预后分析用于开发脑转移 II/III期黑色素瘤患者。随着最近的辅助疗法的批准，包括第三期疾病， 当患有最小或不可检测的疾病时，我们有很大的干预机会，不仅 预防黑色素瘤复发，但也可以提高整体生存率。由于这些辅助疗法并非没有风险，所以 成功完成该项目的目标将通过确定这些目标产生重大的翻译影响 最有可能受益于辅助治疗的患者。