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

尽管dna低甲基化药物（HMAs）由于其良好的毒性特性已获得FDA和EMA的批准，但针对老年、医学上不适合的AML患者的适龄治疗仍然是一个高度未满足的临床需求。然而，有效率和持续时间仍然有限，因此迫切需要更有效的治疗组合。我们在老年非适合AML患者中进行了一项随机临床试验，使用HMA地西他滨联合HDAC抑制剂丙戊酸或全反式维甲酸（ATRA）。接受地西他滨+ ATRA联合治疗的患者在总生存期有明显的获益，即使是那些有不良细胞遗传学的患者。A05项目的总体目标是更好地理解为什么添加ATRA可以改善地西他滨治疗的AML患者的预后，以及我们如何通过添加其他具有良好毒性的药物来推进这种治疗方法。在A05中，我们提出了以下假设：H1：地西他滨和ATRA联合使用对基因调控具有协同作用，这是单独使用任何一种药物都无法实现的；这些效果可以通过添加第三种治疗剂来增强。H2：预处理基因突变和AML细胞DNA甲基化模式可以预测地西他滨+ ATRA治疗的反应。H3：持续地西他滨+ ATRA治疗导致继发性耐药，这与具有不同基因突变和DNA甲基化模式的克隆的发生或选择有关（在地西他滨+ ATRA原发性耐药患者中可能观察到具有相似遗传模式和非遗传模式的克隆）。这些假设将通过以下特定目标来解决：特定目标1：体外建模联合治疗以增强dna低甲基化治疗的抗白血病活性，联合伙伴ATRA， BCL-2抑制剂venetoclax （ABT-199）和LSD1抑制剂homedemstat （IMG-7289）在接受地西他滨和维甲酸治疗的患者中鉴定治疗前遗传和表观遗传反应预测因子特异性Aim 3：揭示和克服对基于dna低甲基化的AML特异性Aim 4治疗的耐药性通过转录组研究和体内治疗来克服MLL-EDC4基因融合的新描述的AML亚型的地西他滨耐药。通过解决这些目标，我们希望更好地了解这种治疗的作用机制，并最终改善预后仍然令人沮丧的患者的预后。

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.