Molecular Basis Of Renal Cell Carcinoma Response to SU11428

转移性透明细胞肾细胞癌（RCC）对常规抗肿瘤药物几乎一致耐药。 肿瘤治疗SU 11248是一种小分子酪氨酸激酶抑制剂， 在转移性RCC中的抗肿瘤活性。我们假设，识别遗传标记的反应， SU 11248治疗将导致新的治疗靶点，定向治疗，并可能改善临床 结果。该提案的总体目标是确定RCC对以下反应的分子标志物： SU 11248，并了解体外良好和不良反应者的生物学反应， 具体目的：（1）筛选预测肾细胞癌对SU 11248反应的分子标志物。RCC 将提交一线SU 11248治疗前从患者中切除的标本进行表达 分析，并识别响应相关的表达式签名。(2)分子标记 预测RCC衍生细胞系对SU 11248的应答。细胞对SU 11248的反应， 将在12个可用的细胞系中测定表达谱，并将应答相关的表达 获得的签名。我们的初步研究表明，五个品系在接种后表现出活力丧失， SU 11248治疗，7个没有。HIF 1A靶基因的表达， VHL是肾细胞癌中常见的标志物，可作为SU 11248治疗反应的预测指标之一。（三） SU 11248应答的分子标志物验证。预测免疫应答的分子标志物 特异性目的1和2将在一组独立的阵列RCC中通过免疫组织化学进行验证。 标本还将在标本中评价HIF 1A靶基因的表达是否相关 有回应。(4)转录反应和信号通路激活的表征 SU 11248反应性和非反应性RCC细胞系。稳定状态水平的全球变化 将在代表性RCC细胞系中评价用SU 11248处理后的转录物， 在时间和功能上进行聚类，以确定可能导致敏感性的下游效应和/或 或抗SU 11248。还将评估下游信号传导通路的激活，以确定 不同表型反应的因果关系。这些基于肿瘤和细胞系的研究奠定了基础， 进一步的分子研究旨在了解RCC对SU 11248的敏感性/抗性。

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.