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

尽管DNA低甲基化剂（HMA）因其良好的毒性特征已获得FDA和EMA批准，但老年、医学上不适合的AML患者的年龄适当治疗仍代表高度未满足的临床需求。然而，缓解率和持续时间仍然有限，因此迫切需要更有效的治疗组合。我们在老年不健康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+全反式维甲酸联合治疗的患者在总生存率方面有明显的益处，即使是那些细胞遗传学不良的患者。A05项目的总体目标是更好地理解为什么加入ATRA可以改善地西他滨治疗的AML患者的结局，以及我们如何通过加入其他具有有利毒性特征的药物来推进这种治疗方法。在A05中，解决了以下假设：H1：地西他滨和ATRA联合使用时，对基因调控具有协同作用，而单独使用任何一种药物都无法实现;这些效果可以通过加入第三种治疗剂来增强。H2：AML细胞治疗前基因突变和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，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相关（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和非遗传模式的克隆）。这些假设将通过以下特定目的来解决：特定目的1：联合治疗的体外建模，以增强DNA低甲基化治疗的抗白血病活性，联合伴侣为ATRA、BCL-2抑制剂venetoclax（ABT-199）和LSD 1抑制剂bomedemstat（IMG-7289）具体目标2：在接受地西他滨和视黄酸治疗的患者中确定原发性AML原始细胞的治疗前遗传学和表观遗传学反应预测因子具体目标3：解开和克服对基于DNA低甲基化的AML治疗的抗性转录组研究和体内治疗以克服新描述的具有MLL-EDC 4基因融合的AML亚型的地西他滨耐药性通过解决这些目标，我们希望更好地理解这种治疗的作用机制，并最终改善预后仍然不佳的患者的预后。

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.