Abstract

There is increasing evidence that perturbations in chromatin structure contribute to the pathogenesis of AML raising the possibility that modulators of chromatin structure may be of therapeutic benefit. Sodium valproate (VPA) is a potent histone deacetylase inhibitor (HDI) and in conjunction with ATRA induces apoptosis of primary AML blasts in vitro. It has been postulated that induction of pro-apoptotic genes including p21 and TRAIL play a critical role in determining the tumor selectivity of HDIs. We have therefore conducted a Phase I/II study of combined VPA/ATRA therapy in patients with high risk AML ineligible for chemotherapy and correlated clinical response with alterations in chromatin structure, induction of pro-apoptotic genes and in vitro sensitivity to VPA. In light of evidence that modulating cAMP levels may increase rexinoid responsiveness theophylline was added in patients who had failed to respond to 28 days combined VPA/ATRA therapy. A total of 20 patients (median age 72 yrs) have been treated to date including 12 patients with relapsed AML, 6 with previously untreated disease and 2 with primary refractory disease. Nine patients completed treatment for at least 8 weeks. Four patients (all with relapsed AML) demonstrated a haematological response. One patient achieved a complete remission and two a partial remission. Myeloblasts isolated from trial patients prior to the commencement of therapy demonstrated varying sensitivity to VPA and ATRA in vitro which correlated with clinical response. Combined treatment with VPA and ATRA resulted in increased levels of histone acetylation and methylation and induced expression of p15, p16 and p21 in myeloblasts from treated patients. Induction of TRAIL was documented in three patients-two of whom demonstrated a clinical response. p21 induction was documented in all responding patients. Induction of p21 and TRAIL was most marked in the patient who achieved a CR. There was no apparent correlation between induction of p15 or p16 and response. We have previously documented that exposure of AML cell lines to HDIs results in specific changes in HDAC expression patterns with selective up-regulation of HDAC11 and to a lesser extent HDAC9 and SIRT4. Similar changes in HDAC expression were documented in myeloblasts from patients after 28 days treatment with VPA/ATRA. This study demonstrates that VPA, in combination with ATRA and theophylline, has significant clinical and biological activity and identifies possible mechanisms underlying the tumor-specific activity of VPA in AML in vivo.

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