Poster Presentation 25th Lorne Cancer Conference 2013

Orphan Nuclear Receptor NUR77: A Potential Biomarker of Response to Epigenetic Treatment of Myelodysplasia (#261)

HongBin Liu 1 , David Urbanavicius 1 , Peter Tan 2 , Andrew Spencer 1 2 , Anthony E Dear 1 3
  1. Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia
  2. Haematology, Alfred Hospital, Melbourne, Victoria, Australia
  3. Medicine, Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia

Combination epigenetic treatments utilising demethylating agents and histone deacetylase inhibitors (HDACi) may be more efficacious than single agent treatment in myelodyplastic syndromes (MDS) and acute myeloid leukemia (AML)1.
The orphan nuclear receptor NUR77 is a putative tumour suppressor gene implicated in the pathogenesis of MDS and AML2. Our previous studies have identified up-regulation of NUR77 expression in response to combination epigenetic treatment suggesting a potential molecular mechanism responsible, in part, for the therapeutic effect in MDS and AML3-4.
Our study aimed to identify the effect of epigenetic treatment on patterns of expression of NUR77 and other genes implicated in the pathogenesis of high-risk MDS or AML in patients enrolled in a phase Ib/II clinical trial (http://www.anzctr.org.au/trialview .aspx?ID=335471) using the combination of the HDACi panobinostat (LBH589) and 5-azacytidine and correlate these findings with clinical response to treatment.
Analysis of gene expression at screening and post treatment demonstrated modulation of expression of NUR77, Caspase 3, Nor-1, Bcl-XL and p21WAF1/CIP1 ranging from 1.5 to 4 fold over screening levels. Gene expression patterns suggested a significant and incremental increase in the expression of NUR77.
Given an observed improvement in median survival in those patients responding to treatment correlation of NUR77 expression with clinical response was analysed. Response to treatment was associated with an approximate 4-fold induction of NUR77 expression at day 25 of treatment, an effect not observed in non-responders.
Together these results suggest combination treatment with HDACi and demethylating agents may be a useful treatment in the high risk MDS/AML patient population, is associated with in vivo modulation of genes implicated in the pathogenesis of MDS/AML and expression of the tumour suppressor gene NUR77 may correlate with response to treatment and be a potentially useful biomarker in patients receiving combination epigenetic treatment.

  1. Quintás-Cardama A, Santos FP, Garcia-Manero G. Histone deacetylase inhibitors for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Leukemia. 25:226-35, 2011.
  2. Mullican SE, Zhang S, Konopleva M et al. Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat Med. 13:730-5, 2007.
  3. Liu HB, Voso MT, Gumiero D et al. The anti-leukemic effect of a novel histone deacetylase inhibitor MCT-1 and 5-aza-cytidine involves augmentation of Nur77 and inhibition of MMP-9 expression. Int J Oncol. 34:573-9, 2009.
  4. Liu HB, Wong A, Spencer A and Dear AE. “In vitro and In vivo Effects of Azacytidine Alone and in Combination with the Pan Histone Deacetylase Inhibitor LBH589”. In Proceedings 24th Lorne Cancer Conference, Victoria, Australia. February 9th-16th 2012