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 调节细胞表观遗传模式的药物的效用在肿瘤学中获得了吸引力，部分原因是 报道了对肿瘤细胞的细胞抑制作用。虽然人们对肿瘤细胞的关注很多，但对它们的了解却很少。 对被招募到肿瘤微环境中的免疫细胞的影响。这个问题特别重要。 当考虑到免疫治疗药物的吸引力越来越大，这些药物在癌症中显示出有希望的结果时 其他疗法失败的患者。这样的治疗效果归因于重新振作 免疫细胞的效应器成分。因此，有可能促进免疫细胞功能的药物 而抑制肿瘤微环境中的抑制机制被预测为促进 治疗方面的好处。在这方面，我们发现一种靶向选择组蛋白脱乙酰基酶的抑制剂，以及 溴域蛋白BET家族的一种抑制剂具有显著的免疫调节作用， 支持改善免疫功能。目前的提案将建立在这些发现的基础上，以了解这些 药物的作用，以及如何利用这些独特的特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)了解ACY241和JQ1对肿瘤全球基因网络和表观遗传足迹的影响- 相关的免疫细胞亚群。 (2)评价ACY241和JQ1作为联合用药的治疗潜力。 采用基因工程小鼠模型(GEMM)建立非小细胞肺癌(NSCLC)模型。 (3)评价GEMM测试的新型药物组合对体外生长的患者肿瘤的影响 培养作为临床适用性的衡量标准。

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.