The DNA methylome as a therapeutic target in elderly patients with acute myeloid leukemia: Development of combination treatments

点击翻译按钮获取中文摘要

The age-appropriate therapy of elderly, medically non-fit AML patients still represents a highly unmet clinical need, despite DNA-hypomethylating agents (HMAs) having been FDA- and EMA approved, by virtue of their favorable toxicity profile. However, both response rate and duration are still limited, thus more effective treatment combinations are urgently needed. We have conducted a randomized clinical trial in elderly, non-fit AML patients, with the HMA decitabine, combined with the HDAC inhibitor valproic acid or all-trans retinoic acid (ATRA). Patients receiving the decitabine + ATRA combination had a marked benefit in overall survival, even those with adverse cytogenetics. The overarching goal of the A05 project is to better understand why the addition of ATRA improves the outcome of decitabine-treated AML patients, and how we can advance this treatment approach by adding other agents with a favorable toxicity profile.Within A05, the following hypotheses are addressed: H1: In combination, decitabine and ATRA have cooperative effects on gene regulation not achieved by either drug alone; these effects can be enhanced by addition of a third therapeutic agent. H2: Pretreatment gene mutations and DNA methylation patterns of the AML cells can predict the response to decitabine + ATRA treatment. H3: Continued decitabine + ATRA treatment results in secondary resistance, associated with occurrence or selection of clones with distinct gene mutations and DNA methylation patterns (clones with similar genetic and non-genetic patterns may be observed among patients with primary resistance to decitabine + ATRA). These hypotheses will be addressed by the following Specific Aims: Specific Aim 1: In vitro modeling of combination treatments to enhance the antileukemic activity of DNA-hypomethylating treatment, with the combination partners ATRA, the BCL-2 inhibitor venetoclax (ABT-199), and the LSD1 inhibitor bomedemstat (IMG-7289)Specific Aim 2: Identifying pre-therapeutic genetic and epigenetic response predictors in primary AML blasts from patients treated with decitabine and retinoic acidSpecific Aim 3: Unravelling and overcoming resistance to DNA-hypomethylation based treatment of AMLSpecific Aim 4: Transcriptome studies and in vivo treatment to overcome decitabine resistance of a newly described AML subtype with a MLL-EDC4 gene fusionBy addressing these Aims, we hope to gain a better understanding of the mechanism of action of this treatment, and to ultimately improve the prognosis of patients with a still dismal outcome.