title: Epigenetic resensitization to platinum in ovarian cancer.
abstract: 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.
authors.affiliation: Melvin and Bren Simon Cancer Center, Indiana University, Bloomington, Indiana 46202, USA. dmatei@iupui.edu
authors.forename: Daniela
authors.initials: D
authors.lastname: Matei
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Changyu
authors.initials: C
authors.lastname: Shen
authors.forename: Jeanne
authors.initials: J
authors.lastname: Schilder
authors.forename: Alesha
authors.initials: A
authors.lastname: Arnold
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.forename: William A
authors.initials: WA
authors.lastname: Berry
authors.forename: Tim
authors.initials: T
authors.lastname: Huang
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000235:genetics
chemical_list: D000077209:Decitabine; D016190:Carboplatin; D001374:Azacitidine