Abstract A18: Genome-wide methylation profiling to identify potential epigenetic biomarkers associated with response to sunitinib in metastatic renal cell cancer patients (pts)

Abstract

Abstract Background: Sunitiinib is a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) that is widely used in the front line setting for the treatment of advanced renal cell cancer. As with other targeted agents, there is a significant heterogeneity in the clinical response to sunintib and a biomarker which would predict patients' response up front would be an invaluable tool in the clinical management of patients (pts) afflicted with this disease. In this regard, whole genome methylation array was performed between sunitinib responders and nonresponders to identify differentially methylated genes between these two subsets of pts. Methods: mRCC pts. who received sunitinib therapy with available frozen nephrectomy tissues and clinical data were identified. Responders (RES) were identified as patients with progression free survival (PFS)of >11 months (mos) and nonresponders (NRES) as those with PFS <3 mos. Whole genome methylation array was performed using Infinium Humanmethylation450 BeadChip Kit. The statistical analysis performed was based on one-way ANOVA and an empirical Bayes approach was used to moderate standard errors. The QC plots showed that all arrays were fine and successful. Results: Thirteen pts treated with sunitinib for mRCC with available frozen nephrectomy tissues as well as clinical data were identified. Five were selected for each RES and NRES cohort as described above. Three pts had PFS that ranged between 3-11 mos (INT). All pts. In RES had clear cell subtype. Two of the NRES group were of non-clear cell type. For RES vs. NRES, one genomic location, DENND2D, was significantly hypermethylated in the RES group with a false discovery rate (FDR) of <10%. For RES+INT vs NRES, DENND2D hypermethylation was also seen in the RES+INT group but 4 other genes (TTYH3, TRAPPC12, HLA-DRB6 and cg15042082) were shown to be hypermethylated in the NRES group, also with a FDR<10%. Conclusion: In this study, DENND2D was significantly hypermethylated in sunitinib RES vs. NRES in mRCC pts. Technical and clinical validation of DENND2D and the other 4 differentially methylated genes are planned as is immunohistochemistry study of DENND2D to evaluate downstream effects of methylation. Citation Format: Jenny Kim, Mariette Labots, Henk Verheul, Michael Carducci, Shahnaz Begum, George Netto, Mohammad Hoque. Genome-wide methylation profiling to identify potential epigenetic biomarkers associated with response to sunitinib in metastatic renal cell cancer patients (pts). [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A18.