Methylation and histone deacetylase inhibition in combination with platinum treatment in patients with advanced malignancies

Abstract

Purpose The combination of DNA methylation inhibitors and histone deacetylase inhibitors is synergistic in gene expression activation and may overcome platinum resistance. Sequential treatment with azacitidine and valproic acid (VPA) in combination with carboplatin may overcome resistance to platinum-based therapy, and we conducted a phase I trial to assess safety, maximum tolerated dose (MTD), and clinical correlates. Experimental Design Patients with advanced solid tumors refractory to standard therapy were eligible. In cohorts of escalating doses, patients received azacitidine for 5 days from days 1 to 5, VPA for 7 days from days 5 to 11, and carboplatin starting in the second cycle on days 3 and 10. Clinical correlates included evaluation of epigenetic changes, methylation patterns, and histone acetylation levels in peripheral blood mononuclear cells. Results Thirty-two patients were treated. The MTD was 75 mg/m2 azacitidine, 20 mg/kg VPA, and AUC 3.0 carboplatin. Minor responses or stable disease lasting ≥4 months were achieved by six patients (18.8%), including three with platinum-resistant or platinum-refractory ovarian cancer. The most common adverse events grade ≥3 were fatigue (81%) and neutropenia (69%). Dose-limiting toxicity occurred in six patients (18.8%), including four patients with grade 3 altered mental status. Death receptor 4 (DR4) methylation was shown to decrease in a subset of patients, but there was no relationship with tumor response or number of cycles received. Conclusions Combination of azacitidine, VPA, and carboplatin demonstrates decreased DR4 methylation and modest evidence of antitumor activity in patients with heavily treated advanced malignancies.

Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells

“…One solution was to combine multiple drugs that act synergistically. A number of ongoing clinical trials are investigating the effects of combined therapy against different types of cancer (25)(26)(27). In our experimental system, the effect of combined treatment with SAHA and PJ34 on TXNIP expression was associated with variation in cell viability and apoptosis.…”

Cardiovascular effects of histone deacetylase inhibitors epigenetic therapies: Systematic review of 62 studies and new hypotheses for future research

“…1 and Table 1). The included studies examining the different HDACi were divided as follows: 22 studies for Romidepsin , 14 for Panobinostat [33][34][35][36][37][38][39][40][41][42][43][44][45][46], 14 for Vorinostat [47][48][49][50][51][52][53][54][55][56][57][58][59][60], 7 for Belinostat [61][62][63][64][65][66][67], 4 for Valproate [68][69][70][71] and 1 for Entinostat [6]. A total of 3268 patients were identified from 62 studies, and were subsequently divided into six HDACi specific groups for subgroup analyses.…”

New insights into the epigenetic control of satellite cells

“…Several drugs that target epigenetic mechanisms are currently undergoing clinical trials for many diseases. These drugs include HDAC inhibitors [101] and HMT inhibitors alone [102] or in combination [103] . In amyotrophic lateral sclerosis, HDAC inhibitors have been proposed as potential drugs to ameliorate patient symptoms [104,105] .…”