Investigating mechanistic underpinnings and therapeutic potential of selective histone deacetylase and bromodomain inhibition for the treatment of non-small cell lung cancer

项目摘要 调节细胞中表观遗传模式的药物的效用在肿瘤学中越来越受欢迎，部分原因是 报道了对肿瘤细胞的细胞生长抑制作用。虽然人们对肿瘤细胞的关注很多，但对它们的生物学特性知之甚少。 对募集到肿瘤微环境的免疫细胞的影响。这个问题特别重要 当考虑到对癌症显示出有希望的结果的免疫药物越来越有吸引力时， 其他治疗失败的患者。这样的治疗结果归因于恢复活力， 免疫细胞的效应成分。因此，具有促进免疫细胞功能潜力的药剂 虽然预测肿瘤微环境内的抑制机制会促进 治疗益处。在这方面，我们已经发现靶向选择组蛋白脱乙酰酶的抑制剂， 一种BET家族布罗莫结构域蛋白的抑制剂显示出显著的免疫调节作用， 增强免疫功能。目前的建议将建立在这些调查结果，以了解如何这些 药物的工作，以及如何利用这些独特的属性来治疗非小细胞肺癌 采用合理的联合用药方案。因此，提出了以下目标： (1)为了了解ACY241和JQ1对肿瘤中全球基因网络和表观遗传足迹的影响， 相关免疫细胞亚群。 (2)评价ACY 241和JQ 1作为联合治疗中的伴侣药物的治疗潜力， 非小细胞肺癌（NSCLC）的基因工程小鼠模型（GEMM）。 (3)评价在GEMM中测试的新型药物组合对离体增殖的患者肿瘤的作用 作为临床应用的衡量标准。

Project Summary The utility of drugs that regulate epigenetic patterns in cells are gaining traction in oncology in part due to reported cytostatic effect on tumor cells. While much attention is on tumor cells, little is known about their effects on immune cells that are recruited to the tumor microenvironment. This issue is of particular importance when considering the increasing appeal of immunotherapeutic drugs which show promising results in cancer patients where other therapies have failed. Such therapeutic outcomes are attributed to re-invigoration of effector components of immune cells. Thus agents which have the potential to promote immune cell function while dampening inhibitory mechanisms within the tumor microenvironment are predicted to promote therapeutic benefits. In this regard, we have found that an inhibitor targeting select histone deacetylases, and an inhibitor of the BET family of bromodomain protein exhibit remarkable immune-modulating effects that support improved immune function. The current proposal will build on these findings to understand how these drugs work, and how these unique properties can be leveraged for treatment of non-small cell lung cancer using rational combinatorial drug regimen. Thus, the following aims are proposed: (1) To understand the effect of ACY241 and JQ1 on global gene networks and epigenetic footprints in tumor- associated immune cell subsets. (2) To evaluate the therapeutic potential of ACY241 and JQ1 as partner agents in combinatorial therapy for non-small cell lung cancer (NSCLC) using genetically engineered mouse model (GEMM). (3) To evaluate the effects of novel drug combinations tested in GEMM on ex-vivo propagated patient tumor cultures as a gauge for clinical applicability.