MP35-15 DEVELOPING A PATIENT-DERIVED XENOGRAFT MODEL USING CHICKEN EMBRYOS TO PREDICT TARGETED THERAPY TUMOR RESISTANCE IN RENAL CELL CARCINOMAS

METHODS: Comparative gene expression analysis by mRNA microarray demonstrates a marked increase in the expression of Pyruvate Dehydrogenase Kinase-1 (PDK-1) in metastatic RCC compared with both normal tissue and primary RCC. PDK-1 promotes glycolytic metabolism by blocking the entry of pyruvate into the TCA cycle thereby inhibiting oxidative phosphorylation. Based on these data, we investigated the contribution of PDK-1 overexpression to therapy resistance utilizing two pharmacologic inhibitors of PDK-1, dichloroacetate (DCA) and phenylbutyrate (PB). RCC cell lines A498 and 786-O were exposed to Sorafenib only and PDK-1 inhibitors (DCA or PB) alone in order to determine the drug-response relationship. Minimally inhibitory doses of PDK-1 inhibitors were then used in combination with increasing doses of Sorafenib. MTS assays were performed in each experimental design in order to determine cell proliferation and viability. In tandem, Annexin V staining was utilized to determine the contribution of apoptosis to cell death following treatments. RESULTS: PDK-1 inhibition with either DCA or PB sensitized 786-O RCC cells to the cytotoxic effect of sorafenib. These data reached statistical significance (p<0.05). Similarly, PB sensitized A498 cells to sorafenib (p<0.05). Furthermore, the differences in cell viability between control groups (no treatment) and PDK-1 inhibitor (DCA or PB) alone were not statistically significant. Annexin V staining revealed significantly increased apoptosis with sorafenib/PB cotreatment when compared to Sorafenib alone. CONCLUSIONS: Activation of the TCA cycle via inhibition of PDK-1 potentiates the anti-tumor activity of Sorafenib. Although further characterization of the role of PDK-1 inhibitors in tumor growth suppression is required, our preliminary data suggests an important role of the Warburg effect demonstrated by RCC in the development of treatment resistance. Furthermore, unlocking metabolic pathways associated with this phenomenon may be the key to a novel therapeutic approach in the treatment of RCC. Rising Star Award-Urology Care Foundation