Co-targeting BET Bromodomain Proteins and MNK Kinases in Pancreatic Cancer

越来越多的研究表明，针对溴域和末端外的抑制剂 介导mRNA转录的结构域(BET)蛋白对胰腺导管具有抗肿瘤作用 腺癌(PDAC)。BET抑制剂还可以通过抑制PDAC间质的激活使PDAC间质正常化。 肿瘤相关成纤维细胞(CAF)。然而，BET抑制剂诱导Rac1介导的MNK激活 激酶，它介导了信使核糖核酸的翻译。重要的是，靶向MNK激酶和MNK效应因子hnRNPA1 增强BET抑制剂的功效。值得注意的是，MNK抑制剂诱导CD8T细胞浸润，但他们的 肿瘤相关巨噬细胞(TAMs)抑制效应器功能。值得注意的是，BET抑制剂可以 减少TAMs的入渗。本申请的目的是阐明 BET和MNK抑制剂联合应用显示了对PDAC的抗肿瘤反应。中环 假说是这种组合有效地靶向癌细胞，调节肿瘤免疫。 微环境，并使胰腺间质正常化以抑制PDAC生长。三个具体目标是 建议：1)定义和定位负反馈环以增强BET抑制剂的抗肿瘤作用 2)评价BET和MNK抑制剂联合应用对CD8T细胞的影响。 BET和MNK抑制剂联合应用对胰腺间质的影响。 在第一个目标下，MNK效应分子hnRNPA1和CYFIP1发挥作用的机制 在Rac1下游，LIMIT BET抑制剂的疗效将得到评估。此外，联合治疗的疗效 使用BET和MNK抑制剂将在有机和转基因的PDAC小鼠模型中进行评估。对于 目的二、联合治疗对CD8T细胞浸润活化及巨噬细胞的影响 丰度和极化将被评估。此外，MNK激酶和MNK效应器的作用 将评估hnRNPA1和CYFIP1在巨噬细胞中限制BET抑制剂的疗效。在第三节 目的：研究联合治疗对转基因小鼠间质反应的影响。 模特。胰腺CAF中MNK激酶、CYFIP1和hnRNPA1在限制胰腺CAF疗效中的作用 Bit抑制剂也将接受评估。此外，BET与MNK激酶活性、MNK的关系 效应物和间质反应将在人PDAC肿瘤标本中进行评估。有几个创新之处 该提案中的要素，包括增强PDAC抗肿瘤反应的新治疗方法 患者；BET和MNK抑制剂联合治疗如何调节肿瘤的新概念 协同抗肿瘤反应的免疫微环境和间质反应； PDAC复杂模型的组合，包括体内原位模型、器官模型和转基因小鼠模型。 这项拟议的研究具有重要的意义，因为它将具有重要的临床翻译意义，并且应该 结果为PDAC患者开发了新的联合治疗方法。

A growing body of research has now demonstrated that inhibitors targeting bromodomain and extra-terminal domain (BET) proteins, which mediate mRNA transcription, have anti-tumor effects against pancreatic ductal adenocarcinoma (PDAC). BET inhibitors can also normalize the PDAC stroma by suppressing the activation of cancer-associated fibroblasts (CAFs). However, BET inhibitors induce Rac1-mediated activation of MNK kinases, which mediate mRNA translation. Importantly, targeting MNK kinases and the MNK effector hnRNPA1 enhances the efficacy of BET inhibitors. Significantly, MNK inhibitors induce CD8+ T cell infiltration, but their effector function is suppressed by the tumor-associated macrophages (TAMs). Notably, BET inhibitors can decrease the infiltration of TAMs. The objective in this application is to elucidate the mechanisms by which the combination of BET and MNK inhibitors demonstrates anti-tumor responses against PDAC. The central hypothesis is that the combination effectively targets the cancer cells, modulates the tumor immune microenvironment, and normalizes the pancreatic stroma to suppress PDAC growth. Three specific aims are proposed: 1) Define and target negative feedback loops to enhance the anti-tumor effects of BET inhibitors in vivo; 2) Evaluate the effects of the combination of BET and MNK inhibitors on CD8+ T cell infiltration and activation; 3) Determine the effects of the combination of BET and MNK inhibitors on the pancreatic stroma. Under the first aim, the mechanisms by which MNK effectors hnRNPA1 and CYFIP1, which can function downstream of Rac1, limit the efficacy of BET inhibitors will be evaluated. Further, the efficacy of co-treatment with BET and MNK inhibitors will be evaluated in organoid and transgenic mouse models of PDAC. For the second aim, the effects of the combination therapy on CD8+ T cell infiltration and activation and macrophage abundance and polarization will be evaluated. In addition, the contribution of MNK kinases and the MNK effectors hnRNPA1 and CYFIP1 in macrophages to limiting the efficacy of BET inhibitors will be evaluated. In the third aim, the effects of the combination therapy on the stromal reaction will be characterized in the transgenic mouse model. The contribution of MNK kinases, CYFIP1, and hnRNPA1 in pancreatic CAFs to limiting the efficacy of BET inhibitors will also be evaluated. In addition, the relationship between BET and MNK kinase activity, MNK effectors, and stromal reaction will be evaluated in human PDAC tumor specimens. There are several innovative elements in this proposal, including the novel therapeutic approach to enhance anti-tumor responses in PDAC patients; novel concepts on how the combination therapy of BET and MNK inhibitors modulates the tumor immune microenvironment and the stromal reaction for synergistic anti-tumor responses; and the unique combination of complex models of PDAC, including in vivo orthotopic, organoid, and transgenic mouse models. This proposed research is significant because it will have important clinical-translational implications and should result in the development of novel combination therapies for PDAC patients.