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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.