Molecular Basis Of Renal Cell Carcinoma Response to SU11428

描述（由申请人提供）：转移性透明细胞肾细胞癌（RCC）对常规抗肿瘤治疗表现出几乎一致的耐药性。SU11248是一种小分子酪氨酸激酶抑制剂，在转移性RCC中显示出高水平的抗肿瘤活性。我们假设鉴定对SU11248治疗反应的遗传标记将导致新的治疗靶点，定向治疗，并可能改善临床结果。本课题的总体目标是确定RCC对SU11248反应的分子标记，了解体外反应良好和不良反应者的生物学反应，具体目的如下：(1)确定预测RCC对SU11248反应的分子标记。在接受一线SU11248治疗之前，从患者身上切除的RCC标本将被提交进行表达谱分析，并确定与反应相关的表达特征。(2)预测rcc来源细胞系对SU11248反应的分子标记的鉴定。将在12个可用的细胞系中确定对SU11248的细胞应答和表达谱，并获得应答相关的表达特征。我们的初步研究表明，5个品系在SU11248处理后表现出活力丧失，7个品系没有。HIF1A靶基因的表达是RCC中常见的VHL失活的结果，被认为是SU11248反应的一组预测标记。(3) SU11248应答分子标记的验证。特异性Aims 1和特异性Aims 2中预测反应的分子标记将在一组独立排列的RCC标本中通过免疫组织化学进行验证。还将在标本中评估HIF1A靶基因的表达与反应的关系。(4) SU11248应答性和非应答性RCC细胞系的转录应答和信号通路激活特性。将在代表性的RCC细胞系中评估SU11248治疗后转录本稳态水平的全局变化，并在时间和功能上进行聚类，以确定可能导致SU11248敏感性和/或耐药性的下游效应。下游信号通路的激活也将被评估，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为进一步的分子研究奠定了基础，旨在了解RCC对SU11248的敏感性/耐药性。

DESCRIPTION (provided by applicant): 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 anti-tumor 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 5 lines exhibit loss of viability after SU11248 treatment, and 7 do not. Expression of HIF1A target genes, a consequence of inactivation of VHL frequently found in RCC, was indicated to be 1 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.