Cited by 391Ovarian cancer diagnosis and treatmentEpigenetics and DNA MethylationMetal complexes synthesis and properties

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Epigenetic Resensitization to Platinum in Ovarian Cancer

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Matei, Daniela, Fang, Fang, Shen, Changyu, Schilder, Jeanne, Arnold, Alesha, Zeng, Yan, Berry, William A., Huang, Tim, Nephew, Kenneth P.·2012·Cancer Research

DOI 10.1158/0008-5472.can-11-3909PMC PMC3700422

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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. Cancer Res; 72(9); 2197–205. ©2012 AACR.

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Authors: Matei, D., Fang, F., Shen, C., Schilder, J., Arnold, A., Zeng, Y., Berry, W. A., Huang, T., & Nephew, K. P.
Affiliations: Indiana University Health (US)
Corresponding author: Matei, Daniela
Nephew, Kenneth P.
ORCID: Matei, Daniela
Fang, Fang
Shen, Changyu
Schilder, Jeanne
Zeng, Yan
Berry, William A.
Huang, Tim
Nephew, Kenneth P.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2012-04-30
Volume: 72
Issue: 9
Pages: 2197-2205
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-11-3909
PMC: PMC3700422
OpenAlex: W2151783390
Cited by: 390
References: 56
Citations by year: 2026: 20 · 2025: 11 · 2024: 27 · 2023: 23 · 2022: 21 · 2021: 33 · 2020: 21 · 2019: 38 · 2018: 36 · 2017: 33 · 2016: 35 · 2015: 39 · 2014: 32 · 2013: 18 · 2012: 3
FWCI: 34.25
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
IUScholarWorks (Indiana University) (submittedVersion)
Funders: U.S. Food and Drug Administration
National Cancer Institute (CA113001, R21CA133877, R01CA085289, U54CA113001, CA133877)
Topics: Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
Keywords: ovarian cancer, platinum resistance, decitabine, DNA demethylation, hypomethylating agents, carboplatin, progression-free survival, MLH1, RASSF1A, HOXA10, HOXA11, drug transporters, Wnt signaling, apoptosis, cytokine signaling pathways
MeSH terms: Decitabine, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Female, Humans, Middle Aged, Neoplasm Recurrence, Local, Ovarian Neoplasms, Peritoneal Neoplasms, Carboplatin, Disease-Free Survival, DNA Methylation

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Epigenetic Resensitization to Platinum in Ovarian Cancer

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