Decitabine reactivated pathways in platinum resistant ovarian cancer

Abstract

Combination therapy with decitabine, a DNMTi and carboplatin resensitized chemoresistant ovarian cancer (OC) to platinum inducing promising clinical activity. We investigated gene-expression profiles in tumor biopsies to identify decitabine-reactivated pathways associated with clinical response. Gene-expression profiling was performed using RNA from paired tumor biopsies before and 8 days after decitabine from 17 patients with platinum resistant OC. Bioinformatic analysis included unsupervised hierarchical-clustering, pathway and GSEA distinguishing profiles of “responders” (progression-free survival, PFS>6months) and “non-responders” (PFS<6months). Functional validation of selected results was performed in OC cells/tumors. Pre-treatment tumors from responders expressed genes associated with enhanced glycosphingolipid biosynthesis, translational misregulation, decreased ABC transporter expression, TGF-β signaling, and numerous metabolic pathways. Analysis of post-treatment biopsies from responders revealed overexpression of genes associated with reduced Hedgehog pathway signaling, reduced DNA repair/replication, and cancer-associated metabolism. GO and GSEA analyses revealed upregulation of genes associated with glycosaminoglycan binding, cell-matrix adhesion, and cell-substrate adhesion. Computational findings were substantiated by experimental validation of expression of key genes involved in two critical pathways affected by decitabine (TGF-β and Hh). Gene-expression profiling identified specific pathways altered by decitabine and associated with platinum-resensitization and clinical benefit in OC. Our data could influence patient stratification for future studies using epigenetic therapies.

Functional characterization of a panel of high-grade serous ovarian cancer cell lines as representative experimental models of the disease

“…Cell lines are the most commonly used models to test new drugs, combination therapies and chemoresistance [18, 20, 21]. Since platinum based therapies are the standard of care for OC patients, we proceeded to establish the IC 50 dose for cisplatin in these HGSOC cell lines.…”

IL-6 mediates platinum-induced enrichment of ovarian cancer stem cells

“…Epigenetic alterations play an important role in OCSC and OC chemotherapy resistance, being largely related to repression of tumor-suppressor genes (specifically, chemotherapy-response and differentiation-associated genes) by DNA methylation (4,46,47). HMAs reverse the expression of silenced tumor suppressors and chemosensitize platinum-resistant ovarian tumors, resulting in significant clinical benefit (47)(48)(49)(50). Importantly, epigenetic therapies, especially HMAs, have been demonstrated to reactivate epigenetic silencing in cancer immunotherapy, remove T cell repression, increase effector T cell tumor infiltration, inhibit tumor growth, and improve therapeutic efficacy of immunotherapy, such as anti-PD-1/PD-L1 (51, 52) and NY-ESO-1 vaccine therapy (53).…”

Decitabine inhibits tumor cell proliferation and up‐regulates e‐cadherin expression in Epstein–Barr virus‐associated gastric cancer

“…DAC prolongs the overall survival of patients with myelodysplastic syndrome and acute myeloid leukemia, and combination therapy of anti-cancer agents and DAC improves the prognosis of acute lymphocytic leukemia [Benton et al, 2014;Mayer et al, 2014]. The efficacy of DAC for solid tumors has not been reported [Fang et al, 2014]. However, the demethylating agent can be applied to the treatment of EBVaGC because promoter hypermethylation of the tumor suppressor gene is a key mechanism in the development of EBVaGC [Fukayama and Ushiku, 2011;Nishikawa et al, 2014].…”