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.

新的治疗方法显著改善了黑色素瘤的治疗，但脑转移瘤仍在 治疗失败的主要原因。能够识别哪些患者具有最高的发病风险 用目前的方法，脑转移瘤是非常具有挑战性的。成功地开发出敏感和特异的 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 在这些高危患者中发生转移。基因表达特征已经被证明是 多种癌症类型的预后和转移的先前基因表达谱(GEP)已经发表 治疗黑色素瘤。但其敏感度和特异度以及阳性和阴性预测价值 这些分析仍然不是最理想的，还没有描述特定的分子特征来预测风险。 脑转移瘤。我们分析了多个独立的基因表达数据集，并确定了一系列 有力地预测了脑转移瘤的发展。为了将这一发现转化为临床，我们将优化 福尔马林固定的石蜡包埋组织中最健壮的基因，并将发现与其他相关 疾病进展的生物标志物。最近对黑色素瘤患者转移灶的分析显示， 脑转移瘤的活性磷酸化AKT(PAKT)水平显著高于颅外 转移瘤。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 模型建立，并观察到80%的小鼠肺和脑转移。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特征相结合 变量，将确定那些黑色素瘤患者发展为脑转移的最高风险。我们会 使用我们丰富的患者样本资源来验证我们的假设。同时进行治疗性干预预防脑部疾病 黑色素瘤的转移是我们的长期目标，为了最有效地实施这一目标是至关重要的 我们开发了更准确的方法来确定哪些患者具有最高的发病风险 在这些转移发生之前的转移疾病。这项研究的目标是产生一种临床/分子 黑色素瘤患者脑转移风险的预测指标及其敏感性和特异性 脑转移瘤发生的优化临床/分子预后分析的回顾性研究 在II/III期黑色素瘤患者中。随着最近对包括III期疾病在内的辅助治疗的批准， 我们有很大的机会在有微小或无法检测到的疾病时进行干预，不仅是 防止黑色素瘤复发，还能提高总体存活率。由于这些辅助治疗并不是没有风险， 成功完成本项目中的目标将通过确定以下内容产生重大的翻译影响 最有可能从辅助治疗中受益的患者。