Rational p300/CREBBP KAT inhibition in AML

AML 中合理的 p300/CREBBP KAT 抑制

• 批准号: 510093527
• 负责人: Dr. Daniel Sasca
• 金额: --
• 依托单位: III. Medizinische Klinik und Poliklinik
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/510093527?language=en
• 关键词: Rational; p300; CREBBP; KAT; inhibition

Acute myeloid leukemias (AML) are aggressive blood cancers with a dismal prognosis of only 30% survival rate at 5 years. AML possess an extraordinary capacity to evolve continuously and adapt under treatment. This characteristic is critically controlled through adjustments of epigenetic processes. Along the fact that epigenetic regulators are commonly mutated in AML, this property designates drugs targeting epigenetic modifications as suitable therapies for such cancers. However, clinical trials with single compounds targeting epigenetic modifiers have often disappointed due to either a primary lack of response, or the subsequent acquisition of non-genetic (mechanistic) adaptation. With this project, I intend to avoid a similar outcome for a currently emerging class of epigenetic modulators – p300/CREBBP lysine acetyltransferase (KAT) inhibitors. To do so, we will initially perform a comprehensive mechanistic and functional deconstruction of the p300/CREBBP roles in diverse models of AML, and then conduct an integrative assessment of the effects of p300/CREBBP KAT inhibition in both treatment-naïve and -resistant settings. Methodologically, we will use a series of up-to-date epigenomic, proteomic and functional techniques in multiple orthogonal systems (cell lines, primary human samples and murine models). This integrative approach will show AML type-specific dynamics at chromatin during treatment response and development of resistance, while also minimizing experimental biases. The necessity of such a complex mechanistic deconstruction is emphasized in our preliminary results. These show a previously unanticipated repressive function of p300/CREBBP to counteract a cell-death inducing interferon response in 50% of all tested AMLs. This is surprising, because p300/CREBBP have mostly been studied in AML for their chromatin-activating functions. We show in our preliminary data that the reliance on p300/CREBBP can be enhanced synthetically, for example through chronic inhibition of bromodomain and extraterminal (BET) proteins. We also show that non-genetic resistance to p300/CREBBP inhibitors causes higher dependency on other druggable epigenetic modulators, such as the canonical chromatin remodeling BAF complex. I propose to exploit these insights (and also results that we will obtain in our first parts of this project) by including p300/CREBBP KAT inhibitors in a rational sequential treatment strategy with 3-4 epigenetic inhibitors, and thus guide treatment trajectories in AML by gradually decreasing plasticity. I hypothesize that this project will critically influence the successful clinical implementation of p300/CREBBP KAT inhibitors to treat AML and will further serve as an example for other next-generation epigenetic modulators.

急性髓性白血病（AML）是侵袭性血癌，预后惨淡，5年生存率仅为30%。AML具有持续进化和适应治疗的非凡能力。这种特性是通过调节表观遗传过程来严格控制的。由于表观遗传调控因子在AML中通常发生突变，这一特性使得靶向表观遗传修饰的药物成为治疗此类癌症的合适药物。然而，针对表观遗传修饰剂的单一化合物的临床试验往往令人失望，原因要么是最初缺乏反应，要么是随后获得了非遗传（机械）适应。在这个项目中，我打算避免目前新兴的一类表观遗传调节剂- p300/CREBBP赖氨酸乙酰转移酶（KAT）抑制剂的类似结果。为此，我们将首先对p300/CREBBP在不同AML模型中的作用进行全面的机制和功能解构，然后对p300/CREBBP KAT抑制在treatment-naïve和-耐药环境中的作用进行综合评估。在方法上，我们将在多个正交系统（细胞系，初级人类样本和小鼠模型）中使用一系列最新的表观基因组学，蛋白质组学和功能技术。这种综合方法将在治疗反应和耐药性发展过程中显示AML在染色质上的类型特异性动态，同时也将实验偏差降到最低。我们的初步结果强调了这种复杂的机械解构的必要性。这些结果显示p300/CREBBP在所有测试的aml中具有先前未预料到的抑制功能，以抵消50%的细胞死亡诱导干扰素反应。这是令人惊讶的，因为p300/CREBBP在AML中主要研究其染色质激活功能。我们在我们的初步数据中表明，对p300/CREBBP的依赖可以通过合成增强，例如通过慢性抑制溴域和外端（BET）蛋白。我们还表明，对p300/CREBBP抑制剂的非遗传抗性导致对其他可药物表观遗传调节剂的更高依赖性，例如典型染色质重塑BAF复合物。我建议利用这些见解（以及我们将在本项目第一部分获得的结果），将p300/CREBBP KAT抑制剂纳入3-4个表观遗传抑制剂的合理顺序治疗策略中，从而通过逐渐降低可塑性来指导AML的治疗轨迹。我假设该项目将对p300/CREBBP KAT抑制剂治疗AML的成功临床实施产生重大影响，并将进一步成为其他下一代表观遗传调节剂的范例。