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PDF file - 284K, Supplementary Figure 1: LINE-1 demethylation in PBMC (A and B) and tumor biopsies (C) separated by group (PFS>6months or < 6months). Supplementary Figure 2: Full Heat Map shows all 842 unique hypermethylated genes for PFS >6 months and 283 genes for PFS 6 months vs. < 6 months (P

PDF file - 6.4MB, Full Heat Map shows all 842 unique hypermethylated genes for PFS >6 months and 283 genes for PFS < 6 months. Methylation levels are color coded from green, � value =0, to red, � value =1.

PDF file - 138K, Materials and Methods. Supplementary Table S1: Primers used for pyrosequencing Supplementary Table S2. DAVID Gene ontology (GO) enrichment analysis of differentially demethylated genes after decitabine in phase II PFS>6months vs. PFS0.5; enrichment score>1.81) Supplementary Table 3. DAVID Gene ontology (GO) enrichment analysis of differentially hypermethylated genes before decitabine in phase II R (PFS>6months) vs. NR (PFS0.5; enrichment score>1.81) Figure legends: Supplementary Figure 1: LINE-1 demethylation in PBMC (A and B) and tumor biopsies (C) separated by group (PFS>6months or < 6months). Supplementary Figure 2: Full Heat Map shows all 842 unique hypermethylated genes for PFS > 6 months and 283 genes for PFS < 6 months. Methylation levels are color coded from green, β value =0, to red, β value =1. Supplementary Figure 3: Demethylation induced by decitabine in biopsy samples. (A) A map of enriched functional clusters for genes demethylated by decitabine in biopsy samples based on DAVID functional annotation clustering. The size of the bars and the circles represent the enrichment score and the gene count, respectively. Detailed information regarding lists of gene members of each cluster is provided in Supplementary Table S2. (B) The pathways enriched by unique demethylated genes in the 2 groups. Supplementary Figure 4: HOXA11 methylation levels (A) HOXA11 DNA methylation levels in patient biopsies measured by pyrosequencing on days 1 and 8. Bars/error bars represent mean +/- SD. (B) Treatment induced hypomethylation of HOXA11 in tumor biopsies in patients with PFS > 6 months vs. < 6 months (P < 0.01). Bars/error bars represent mean +/- SD. (C) Baseline methylation levels of HOXA11 in tumors or ascites correlate with PFS.

Preclinical studies have shown that hypomethylating agents reverse platinum resistance in ovarian cancer. In this phase II clinical trial, based upon the results of our phase I dose defining study, we tested the clinical and biologic activity of low-dose decitabine administered before carboplatin in platinum-resistant ovarian cancer patients. Among 17 patients with heavily pretreated and platinum-resistant ovarian cancer, the regimen induced a 35% objective response rate (RR) and progression-free survival (PFS) of 10.2 months, with nine patients (53%) free of progression at 6 months. Global and gene-specific DNA demethylation was achieved in peripheral blood mononuclear cells and tumors. The number of demethylated genes was greater (P < 0.05) in tumor biopsies from patients with PFS more than 6 versus less than 6 months (311 vs. 244 genes). Pathways enriched at baseline in tumors from patients with PFS more than 6 months included cytokine–cytokine receptor interactions, drug transporters, and mitogen-activated protein kinase, toll-like receptor and Jak-STAT signaling pathways, whereas those enriched in demethylated genes after decitabine treatment included pathways involved in cancer, Wnt signaling, and apoptosis (P < 0.01). Demethylation of MLH1, RASSF1A, HOXA10, and HOXA11 in tumors positively correlated with PFS (P < 0.05). Together, the results of this study suggest that low-dose decitabine altered DNA methylation of genes and cancer pathways, restoring sensitivity to carboplatin in patients with heavily pretreated ovarian cancer and resulting in a high RR and prolonged PFS. Cancer Res; 72(9); 2197–205. ©2012 AACR.

Preclinical studies have shown that hypomethylating agents reverse platinum resistance in ovarian cancer. In this phase II clinical trial, based upon the results of our phase I dose defining study, we tested the clinical and biologic activity of low-dose decitabine administered before carboplatin in platinum-resistant ovarian cancer patients. Among 17 patients with heavily pretreated and platinum-resistant ovarian cancer, the regimen induced a 35% objective response rate (RR) and progression-free survival (PFS) of 10.2 months, with nine patients (53%) free of progression at 6 months. Global and gene-specific DNA demethylation was achieved in peripheral blood mononuclear cells and tumors. The number of demethylated genes was greater (P < 0.05) in tumor biopsies from patients with PFS more than 6 versus less than 6 months (311 vs. 244 genes). Pathways enriched at baseline in tumors from patients with PFS more than 6 months included cytokine–cytokine receptor interactions, drug transporters, and mitogen-activated protein kinase, toll-like receptor and Jak-STAT signaling pathways, whereas those enriched in demethylated genes after decitabine treatment included pathways involved in cancer, Wnt signaling, and apoptosis (P < 0.01). Demethylation of MLH1, RASSF1A, HOXA10, and HOXA11 in tumors positively correlated with PFS (P < 0.05). Together, the results of this study suggest that low-dose decitabine altered DNA methylation of genes and cancer pathways, restoring sensitivity to carboplatin in patients with heavily pretreated ovarian cancer and resulting in a high RR and prolonged PFS. Cancer Res; 72(9); 2197–205. ©2012 AACR.

5541^ Background: The triple PDGFRα/β, VEGFR1-3, FGFR1-3 angiokinase inhibitor BIBF 1120 (B) is active in ovarian cancer (OC). This phase I/II trial evaluates tolerability and efficacy of B combine...