Poster Presentation 26th Lorne Cancer Conference 2014

Molecular Markers of Response to Epigenetic Treatment in MDS/AML (#202)

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

Novel epigenetic treatments for myelodysplastic syndrome (MDS) including DNA methyl transferase inhibitors (DNMTi) and potentially histone deacetylase inhibitors (HDACi) are able to improve survival1. However, not all patients’ respond and treatment regimens are often lengthy with responses frequently only observed after several cycles of therapy1. In order to reduce unnecessary treatment exposure, associated complications and delays in commencement of other potentially effective therapies a significant demand exists for molecular markers to improve early prediction of response to epigenetic therapy, particularly as baseline and early treatment associated epigenetic modifications may not inform on this issue2.

Our previous studies have identified up-regulation of several genes including orphan nuclear receptor NUR77, a putative tumour suppressor gene implicated in the pathogenesis of MDS and AML3, 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. Our ongoing study aimed to determine the time frame for response to epigenetic therapy of NUR77 and other relevant genes in patient samples and correlate these findings with subsequent clinical response.
Analysis of gene expression in patient peripheral blood mononuclear cell samples prior to treatment (screening) demonstrated a significant reduction in NUR77 and p21WAF1/CIP1 mRNA expression compared to healthy controls. NUR77 and p21WAF1/CIP1 mRNA expression levels were similar between treatment non-responders and responders at screening. Post treatment (day 25, first cycle) demonstrated a significant increase in expression of both NUR77, and p21WAF1/CIP1 ranging from 1.5 to 6 fold over screening mRNA levels. Importantly a significant increase in NUR77, and p21WAF1/CIP1 mRNA expression together with a trend to increase in p15INK4B expression was observed in subsequent treatment responders compared to non-responders when assessed 3 or 6 months after commencement of therapy.


Together these results suggest NUR77 and p21WAF1/CIP1 may be useful markers of early epigenetic treatment response in patients receiving combination treatment with demethylating agents and HDACi for high risk MDS/AML and may also predict clinical response to therapy.

  1. Fenaux et al. Lancet Oncol. 10:223-32 (2009).
  2. Shen et al. J Clin Oncol. 228:605-13 (2010).
  3. Mullican et al. Nat Med. 13:730-5 (2007).