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

新的治疗方法显着改善了黑色素瘤的管理，但脑转移瘤仍然是一个棘手的问题。 是治疗失败的主要原因能够识别那些处于最高风险的患者， 脑转移对于目前的方法是非常具有挑战性的。成功开发敏感和特异性 用于预测早期黑色素瘤患者脑转移风险的预后方法将使 制定更有效的监测策略和前瞻性试验，用于脑缺血的化学预防 这些高危患者的转移发展。基因表达特征已被证明是 多种癌症类型的预后和转移瘤的先验基因表达谱（GEP）已发表 治疗黑色素瘤然而，敏感性和特异性以及阳性和阴性预测值 这些测定仍然是次优的，并且没有描述用于预测以下风险的特异性分子标记： 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， 有力地预测了脑转移的发展。为了将这一发现转化为临床，我们将优化 福尔马林固定的石蜡包埋组织中最强大的基因，并将研究结果与其他相关基因整合在一起。 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。 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， 将优化的基因表达标记沿着与其它相关的临床和病理学特征相结合， 变量，将确定那些黑色素瘤患者在发展脑转移的最高风险。我们将 利用我们丰富的病人样本来验证我们的假设虽然治疗干预，以防止大脑 转移性黑色素瘤是我们的长期目标，为了最有效地实现这一目标， 我们需要开发更准确的方法来识别那些最有可能发展为 在这些转移发生之前转移疾病。本研究的目的是产生一个临床/分子 黑色素瘤患者脑转移风险的预测因子，并验证 一项回顾性研究中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。随着包括III期疾病在内的辅助治疗最近获得批准， 我们有很大的机会去干预，当疾病很小或检测不到的时候， 预防黑色素瘤复发，并提高总体生存率。由于这些辅助疗法并非没有风险， 成功完成本项目的目标将通过确定以下方面产生重大的转化影响： 最有可能从辅助治疗中获益的患者。

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.