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.
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