Models to predict prognosis and benefit from adjuvant therapy in renal cell carci

描述（由申请人提供）：靶向抗癌药物的成功开发通常与预测分析相结合，从而使患者更有可能从治疗中获益。免疫组织化学通常用于评估药物靶点的表达，但存在主观性和缺乏定量测量的问题。我们开发了一种自动定量分析（AQUA）方法来原位评估蛋白质水平。针对PA-08-134，我们建议扩大AQUA以同时评估肿瘤和内皮细胞，并建立模型来预测佐剂索拉非尼和舒尼替尼治疗肾细胞癌（RCC）的临床获益，以及模型来预测未经治疗患者的预后。传统上，肾细胞癌是一种对全身治疗具有高度耐药性的疾病。然而，多种靶向治疗，包括索拉非尼和舒尼替尼，最近已经彻底改变了转移性肾癌的治疗方法。这两种药物对RCC亚群患者都有效，并且都有一定的毒性。鉴于这些药物在转移性肾细胞癌中的成功，这些药物正在一项名为E2805的大型、随机、双盲、多中心试验中作为辅助疗法进行研究。正在收集所有患者的标本，它们提供了一个独特的机会来开发模型来预测这些药物的临床益处，并在一个非常大的队列的多中心临床试验环境中预测未经治疗的患者的预后。索拉非尼和苏尼替尼有多个靶点，我们的目的是确定最重要的预测标志物。我们将研究血管生成标志物，MAPK通路成员和其他已知靶点。在AQUA的初步研究中，我们发现肿瘤细胞中高水平血管内皮生长因子（VEGF）受体的rcc往往微血管密度较低，生存率较差。我们假设在肿瘤细胞中VEGF受体高表达的患者比微血管密度高的患者更有可能从治疗中获益。我们将扩展AQUA，通过用不同的荧光团掩盖肿瘤和血管，使其能够同时评估肿瘤和血管中的靶标。我们将建立索拉非尼和舒尼替尼所有已知靶点的染色条件，并选择肿瘤、内皮和邻近正常组织中的血管生成介质，使用未治疗的RCC患者的历史队列。然后，我们将在E2805患者的训练集（67%）中评估VHL突变和索拉非尼和舒尼替尼靶点的表达，并为每种药物生成预测模型，并在测试集中进行验证。标准临床协变量和VHL突变状态将被纳入模型。我们还将使用这些分子标记和临床协变量来改善安慰剂治疗患者的当前预后模型。这些模型可用于选择患者进行最佳的RCC辅助治疗（索拉非尼，舒尼替尼或两者都不），这种方法也可以在其他临床环境中进行研究。

DESCRIPTION (provided by applicant): Successful development of targeted anti-cancer drugs is often coupled with predictive assays that enable selective treatment of patients more likely to benefit from therapy. Immunohistochemistry is often used to assess expression of drug targets, but it suffers from subjectivity and lack of quantitative measures. We developed a method for automated, quantitative analysis (AQUA) for assessing protein levels in situ. In response to PA-08-134, we propose to expand AQUA to simultaneously assess tumors and endothelial cells, and develop models to predict clinical benefit from adjuvant sorafenib and sunitinib for renal cell carcinoma (RCC), as well as models to predict prognosis in untreated patients. RCC has traditionally been a disease that is highly resistant to systemic therapy. However, multiple targeted therapies, including sorafenib and sunitinib, have recently revolutionized the approach to metastatic RCC. Both drugs are effective for subsets of RCC patients, and both are associated with some toxicity. Given their success in metastatic RCC, these drugs are being studied as adjuvant therapies in a large, randomized, double blinded, multi-center trial called E2805. Specimens are being collected on all patients, and they offer a unique opportunity to develop models to predict clinical benefit from these drugs and models to predict prognosis in untreated patients in a multi-center clinical trial setting on a very large cohort. Sorafenib and sunitinb have multiple targets, and our purpose is to identify the most important predictive marker/s. We will study angiogenic markers, members of the MAPK pathway and other known targets. In preliminary studies using AQUA, we showed that RCCs with high levels of vascular endothelial growth factor (VEGF) receptors in tumor cells tend to have lower microvessel density and poor survival. We hypothesize that patients with high VEGF receptor expression in TUMOR cells are more likely to benefit from therapy than those with high microvessel density. We will expand AQUA to enable concurrent assessment of targets in tumor and vessels, by masking the tumor and vessels with different fluorophores. We will establish staining conditions for all known targets of sorafenib and sunitinib and select mediators of angiogenesis in tumor, endothelium and adjacent normal tissue using historical cohorts of untreated RCC patients. We will then assess VHL mutations and expression of sorafenib and sunitinib targets in a training set (67%) of E2805 patients and generate predictive models for each of the drugs, to be validated in a testing set. Standard clinical co-variates and VHL mutational status will be incorporated into the model. We will also use these molecular markers and clinical co-variates to improve current prognostic models in the placebo-treated patients. These models can be used to select patients for the optimal adjuvant therapy for RCC (sorafenib, sunitinib or neither), and this approach can be studied in other clinical settings as well.