Phase I Study of Epigenetic Modulation with 5-Azacytidine and Valproic Acid in Patients with Advanced Cancers

Abstract

Purpose: 5-Azacytidine (5-AZA) is a DNA-hypomethylating agent. Valproic acid is a histone deacetylase inhibitor. Combining hypomethylating agents and histone deacetylase inhibitors produces synergistic anticancer activity in vitro and in vivo. On the basis of this evidence, we conducted a phase I study of the combination of 5-AZA and valproic acid in patients with advanced cancers. Experimental Design: 5-AZA was administered s.c. daily for 10 days.Valproic acid was given orally daily with a goal to titrate to plasma levels of 75 to 100 Ag/mL (therapeutic for seizures). Cycles were 28 days long. 5-AZA was started at 20 mg/m 2 and escalated using an adaptive algorithm based on the toxicity profile in the prior cohort (6 + 6 design). Peripheral blood mononuclear cell global DNA methylation and histone H3 acetylation were estimated with the long interspersed nucleotide elements pyrosequencing assay and Western blots, respectively, on days 1and 10 of each cycle when patients agreed to provide them. Results: Fifty-five patients were enrolled. Median age was 60 years (range, 12-77 years). The maximum tolerated dose was 75 mg/m 2 of 5-AZA in combination with valproic acid. Doselimiting toxicities were neutropenic fever and thrombocytopenia, which occurred at a dose of 94 mg/m 2 of 5-AZA. Stable disease lasting 4 to 12 months (median, 6 months) was observed in 14 patients (25%). A significant decrease in global DNA methylation and induction of histone acetylation were observed. Conclusion: The combination of 5-AZA and valproic acid is safe at doses up to 75 mg/m 2 for 5-AZA in patients with advanced malignancies.

Synergistic induction of PI-PLCβ1 signaling by azacitidine and valproic acid in high-risk myelodysplastic syndromes

“…13 That is why several combination therapies are beginning to be tested, either as chemosensitizing agents in association with standard chemotherapy or combination of epigenetic drugs, aiming at reverting methylation of clonal cells. 14,15 Combination of the DNA methyltransferase inhibitor AZA and the HDAC inhibitor valproic acid (VPA) in patients having MDS and belonging to the International Prognostic Scoring System risk group intermediate-2/high is active and associated with a high response rate in these MDS patients, usually with unfavorable prognosis. 16,17 However, at present, there are no valuable parameters, either diseaseassociated or patient-associated, predictive of response to DNA methyltransferase inhibitors or to the combination of DNA methyltransferase inhibitors and HDAC inhibitors, which could be also useful to monitor the efficacy of the treatment, even though current studies focusing on hypomethylation and gene reexpression in MDS are trying to asses the optimal epigenetic drug targets, and the molecular mechanisms underlying clinical response to demethylating therapy.…”

DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors

“…Although the specific cellular effects and predominant molecular targets of 5-AzaC and Vorinostat in Group 1 CNS-PNET tumor cells need to be further studied in preclinical models, it is interesting to note that synergistic effects without additional toxicities have been reported with combined DNMT and HDAC inhibitor therapy in other cancers [18]. In addition to mTOR inhibitors, our prior studies suggest that inhibitors of the WNT pathway may be additional promising therapeutics for tumors driven by C19MC [3].…”

Genetic Diversity, Epigenetic Reprogramming and Environmental Factors: Leading Directions in the Study of the Complex Human Diseases

“…(80,81) Thus, despite the risk presented by inherited genes and mutations, epigenetic factors play a decisive role in the actual development of disease. Investigation of epigenetic profiling can help in determining the risk of developing a specific disease in an individual with a particular type of genotype.…”