Genotype and phenotype predictors in therapy response in renal cell carcinoma

描述(申请人提供)：近年来，肾细胞癌(RCC)的治疗因靶向药物的疗效而发生变化，靶向药物抑制关键细胞信号通路中涉及的激酶和血管内皮生长因子(VEGF)，血管内皮生长因子是肿瘤血管生成的主要驱动力。然而，患者对这些疗法的反应是高度可变的，目前无法根据临床或病理数据或现有的实验室/基因测试进行预测。这项建议的目标是基于新的测试，为最常见的肾癌亚型--透明细胞癌(CcRCC)的患者开发治疗反应的预测因子。我们的方法主要基于这样的假设，即ccRCC治疗中使用的靶向药物-贝伐单抗、舒尼替尼和索拉非尼-抑制肿瘤血管的激活，并且肿瘤血管的激活状态和稳定性是反应的主要决定因素。我们还假设ccRCC肿瘤血管的表型与肿瘤细胞的分子病理生物学有关。特别是，由于这些药物还可以抑制肿瘤细胞信号并调节其行为，ccRCC肿瘤细胞信号、HIF-1/HIF-2(缺氧诱导因子)表达和VHL功能是潜在的反应决定因素。为了检测血管表型、肿瘤细胞表型和VHL基因型等参数作为治疗反应的预测因子，ccRCC标本将接受适当生物标记物抗原的多重免疫染色，并通过一种新的计算机辅助图像分析系统进行分析，该系统在细胞(细胞学)基础上和传统的基于像素的分析基础上客观地量化分析物染色。这些研究将在正在进行的多机构第二阶段(ECOG2804)和第三阶段(ECOG2805)临床试验中对接受单一药物贝伐单抗、舒尼替尼或索拉非尼治疗的ccRCC患者的肿瘤进行，使用来自90、170和170名合适的ccRCC患者的子集的肿瘤块分别用各自的药物进行治疗。这项建议的具体目的是(1)分析ccRCC肿瘤中血管和内皮细胞的激活表型和血管周细胞的覆盖率；(2)分析ccRCC肿瘤中的肿瘤细胞信号、HIF表型和VHL基因；(3)利用生物统计学和生物信息学的方法，将先前目标中量化的参数与彼此之间的关系、与治疗结果的关系进行关联，并建立简明的治疗反应预测模型。这些研究的结果应该能够确定治疗单个慢性肾细胞癌患者的最合适的药物，并有助于合理开发二线和联合药物疗法。除了ccRCC，正在研究的靶向药物还用于治疗数量不断增加的癌症，为ccRCC开发的反应预测器可能有助于预测这些其他癌症对结合靶向药物的联合治疗的反应。在ccRCC中，这些药物被作为单一药物使用，因此研究得最好。公共卫生相关性：新的靶向癌症治疗药物在治疗肾癌(肾细胞癌)方面取得了成功，肾癌是一种发病率正在上升的癌症，每年有超过5万名美国人被诊断为肾癌。该项目的研究将表征肾细胞癌的肿瘤、血管特征和遗传缺陷，并将它们与治疗反应相关联，以确定可以预测它们是否对治疗有反应的因素。发现肾癌的特征可以预测治疗反应，然后可以用来在未来对患者进行不同的治疗 并将提供可能适用于使用相同新药治疗的许多其他癌症的经验教训。

DESCRIPTION (provided by applicant): Therapy of renal cell carcinoma (RCC) has been transformed in recent years by the efficacy of targeted agents that inhibit kinases involved in critical cellular signaling pathways and VEGF, a primary driver of tumor angiogenesis. However, patient response to these therapeutics is highly variable and currently cannot be predicted based on clinical or pathological data or available laboratory/genetic testing. The goal of this proposal is to develop predictors of therapeutic response for patients with the most common subtype of RCC, clear cell (ccRCC), based on novel tests. Our approach is based primarily on the hypothesis that the targeted agents used in ccRCC therapy - bevacizumab, sunitinib and sorafenib - inhibit tumor vessel activation and that the activation status and stability of tumor vessels are major determinants of response. We also hypothesize that the phenotype of ccRCC tumor vessels is linked to the molecular pathobiology of the tumor cells. In particular, as these drugs also can inhibit tumor cell signaling and modulate their behavior, ccRCC tumor cell signaling, HIF-1/HIF-2 (hypoxia-inducible factor) expression and VHL function are potential determinants of response. To examine parameters of vascular phenotype, tumor cell phenotype and VHL genotype as predictors of response to therapy, ccRCC specimens will undergo multiplex immunostaining for the appropriate biomarker antigens and be analyzed by a novel computer-assisted image analysis system that objectively quantifies analyte staining on a cellular (cytometric) basis as well as by traditional pixel-based analysis. These studies will be performed on tumors of ccRCC patients treated with single-agent bevacizumab, sunitinib or sorafenib in ongoing multi-institutional phase II (ECOG2804) and phase III (ECOG2805) clinical trials, using tumor blocks from a subset of 90, 170 and 170 appropriate ccRCC patients for therapy with the respective drugs. The specific aims of this proposal are (Aim 1) to analyze the vascular and endothelial cell activation phenotype and vessel pericyte coverage in ccRCC tumors; (Aim 2) to analyze tumor cell signaling, HIF phenotype and VHL genotype in ccRCC tumors; and (Aim 3) to correlate parameters quantified in the prior aims for relationships to each other, to therapeutic outcome and to develop parsimonious predictive models of therapeutic response using biostatistical and bioinformatics approaches. The results of these studies should allow identification of the most appropriate drugs for treating individual patients with ccRCC and assist in the rational development of second-line and combination drug therapies. Beyond ccRCC, the targeted agents under study are used in the therapy of an ever expanding number of cancers, and the response predictors developed for ccRCC, where these agents are best studied because they are used as single-agents, may be useful for predicting response of these other cancers to combination therapy incorporating the targeted agents. PUBLIC HEALTH RELEVANCE: Novel targeted cancer therapy agents have shown success in the treatment of kidney cancer (renal cell carcinoma), a cancer that is increasing in incidence and newly diagnosed in over 50,000 Americans a year. Studies in this project will characterize the tumor blood vessel characteristics and genetic defect of renal cell carcinomas and correlate them with therapeutic response to identify factors that can predict whether they will respond to treatment. Discovering features of kidney cancer that predict therapeutic response can then be used to stratify patients to different therapies in the future and will provide lessons that are likely to be applicable to many other cancers being treated with the same novel drugs.