Molecular Basis Of Renal Cell Carcinoma Response to SU11428

转移性肾透明细胞癌(RCC)对常规抗肿瘤药物的耐药性几乎一致。 肿瘤治疗。SU11248是一种小分子酪氨酸激酶抑制剂，它显示出高水平的 转移性肾细胞癌的抗肿瘤活性。我们假设识别遗传标记是为了响应 SU11248治疗将带来新的治疗靶点，定向治疗，并有可能改善临床 结果。这项建议的总体目标是确定肾细胞癌对 SU11248，并了解良好和不良反应者在体外的生物反应，具体如下 具体目的：(1)筛选预测肾癌对SU11248反应的分子标记。碾压混凝土 在一线SU11248治疗前从患者身上切除的样本将提交表达 简档分析和识别的与响应相关联的表达签名。(2)分子标记的鉴定 预测肾癌来源的细胞系对SU11248的反应。细胞对SU11248和 表达谱将在12个可用细胞系中确定，并与反应相关的表达 已获得签名。我们的初步研究表明，五个品系在 SU11248治疗，七个不治疗。HIF1a靶基因的表达，一种失活的结果 肾细胞癌中常见的VHL被认为是SU11248应答的一组预测标志之一。(3) SU11248应答的分子标记验证。预测免疫应答的分子标记物 特定的AIMS 1和2将在一组独立排列的RCC中通过免疫组织化学进行验证 标本。HIF1a靶基因的表达也将在样本中进行评估以进行关联。 并作出回应。(4)转录反应和信号通路激活的特征 SU11248反应性和非反应性肾细胞癌细胞系。稳态水平的全球变化 用SU11248处理后的转录本将在具有代表性的肾癌细胞系中进行评估，以及 在时间和功能上聚在一起，以确定可能的下游影响，从而对敏感性和/或 或对SU11248的抗药性。还将对下游信号通路的激活进行评估，以确定 不同表型反应之间的因果关系。这些以肿瘤和细胞系为基础的研究为 进一步的分子研究旨在了解肾细胞癌对SU11248的敏感性/耐药性。

Metastatic clear-cell renal cell carcinoma (RCC) exhibits a near uniform resistance to conventional anti- tumor therapies. SU11248 is a small molecule tyrosine kinase inhibitor that demonstrated a high level of antitumor activity in metastatic RCC. We hypothesize that identification of genetic markers for response to SU11248 therapy will lead to new therapeutic targets, directed therapy, and potentially an improved clinical outcome. The overall goals of this proposal are to identify molecular markers of the response of RCC to SU11248, and to understand the biologic response of good and poor responders in vitro, with the following specific aims: (1) Identification of molecular markers predictive of response of RCC to SU11248. RCC specimens resected from patients prior to first-line SU11248 therapy will be submitted to expression profiling, and response-associated expression signatures identified. (2) Identification of molecular markers predictive of response of RCC-derived cell lines to SU11248. The cellular response to SU11248 and expression profiles will be determined in 12 available cell lines and the response-associated expression signatures obtained. Our preliminary studies have indicated that five lines exhibit loss of viability after SU11248 treatment, and seven do not. Expression of HIF1A target genes, a consequence of inactivation of VHL frequently found in RCC, was indicated to be one set of predictive markers of SU11248 response. (3) Validation of molecular markers of SU11248 response. The molecular markers predictive of response in Specific Aims 1 and 2 will be validated by immunohistochemistry in an independent set of arrayed RCC specimens. The expression of HIF1A target genes will also be evaluated in the specimens for association with response. (4) Characterization of the transcriptional response and signaling pathway activation of SU11248 responsive and non-responsive RCC cell lines. Global changes in the steady state levels of transcripts following treatment with SU11248 will be evaluated in representative RCC cell lines, and temporally and functionally clustered to identify possible downstream effects responsible for sensitivity and/ or resistance to SU11248. Activation of downstream signaling pathways will also be evaluated to determine causality in the different phenotypic responses. These tumor and cell line-based studies lay a foundation for further molecular studies aimed at understanding the sensitivity/resistance of RCC to SU11248.