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

胰腺癌中 BET 溴结构域蛋白和 MNK 激酶的共同靶向

基本信息

批准号：
10338560
负责人：
Hidayatullah G. Munshi
金额：
$ 49.05万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10338560
关键词：
Antitumor Response Binding Bromodomain CD8-Positive T-Lymphocytes Cells Chronic Clinical Clinical Trials Collagen Combined Modality Therapy Complex Data Development Elements Eukaryotic Initiation Factors Feedback Fibroblasts Genetic Transcription Genetic Translation Goals Growth Histone Acetylation Human Immunotherapy Infiltration Lead Malignant Neoplasms Malignant neoplasm of pancreas Mediating Messenger RNA Mission Organoids Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phosphotransferases Protein Family Proteins Public Health Publishing Reaction Reader Regimen Research Resistance development Role Solid Neoplasm Specimen Stromal Cells Tertiary Protein Structure Testing Transgenic Mice Tumor-associated macrophages Tumor-infiltrating immune cells United States National Institutes of Health antitumor effect base cancer cell effector T cell expectation improved outcome in vivo ineffective therapies inhibitor innovation insight interest macrophage mouse model novel novel therapeutic intervention novel therapeutics pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model programmed cell death ligand 1 programmed cell death protein 1 tumor tumor growth tumor-immune system interactions

项目摘要

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.

越来越多的研究现已证明，针对溴结构域和额外末端的抑制剂介导 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 基质的激活来使 PDAC 基质正常化。癌症相关成纤维细胞（CAF）。然而，BET 抑制剂会诱导 Rac1 介导的 MNK 激活激酶，介导 mRNA 翻译。重要的是，针对 MNK 激酶和 MNK 效应子 hnRNPA1 增强 BET 抑制剂的功效。值得注意的是，MNK 抑制剂诱导 CD8+ T 细胞浸润，但它们的效应器功能受到肿瘤相关巨噬细胞（TAM）的抑制。值得注意的是，BET 抑制剂可以减少 TAM 的渗透。本申请的目的是阐明该机制 BET 和 MNK 抑制剂的组合显示出针对 PDAC 的抗肿瘤反应。中央假设该组合有效地靶向癌细胞，调节肿瘤免疫微环境，并使胰腺基质正常化以抑制 PDAC 生长。三个具体目标是建议：1）定义并瞄准负反馈回路，以增强 BET 抑制剂的抗肿瘤作用体内； 2) 评估BET和MNK抑制剂联合使用对CD8+ T细胞浸润的影响激活; 3)确定BET和MNK抑制剂的组合对胰腺基质的影响。在第一个目标下，MNK效应器hnRNPA1和CYFIP1发挥作用的机制 Rac1的下游，限制BET抑制剂的功效将被评估。此外，联合治疗的疗效将在 PDAC 类器官和转基因小鼠模型中评估 BET 和 MNK 抑制剂的效果。对于第二个目标，联合治疗对CD8+T细胞浸润和活化以及巨噬细胞的影响将评估丰度和极化。此外，MNK 激酶和 MNK 效应器的贡献将评估巨噬细胞中的 hnRNPA1 和 CYFIP1 对限制 BET 抑制剂功效的影响。在第三个目的，将在转基因小鼠中表征联合疗法对基质反应的影响模型。 MNK 激酶、CYFIP1 和 hnRNPA1 在胰腺 CAF 中对限制 CAF 疗效的作用 BET 抑制剂也将被评估。另外，BET与MNK激酶活性、MNK的关系将在人类 PDAC 肿瘤标本中评估效应器和基质反应。有几个创新点该提案中的要素，包括增强 PDAC 抗肿瘤反应的新治疗方法患者;关于 BET 和 MNK 抑制剂联合治疗如何调节肿瘤的新概念免疫微环境和基质反应以实现协同抗肿瘤反应；和独特的 PDAC 复杂模型的组合，包括体内原位、类器官和转基因小鼠模型。这项拟议的研究意义重大，因为它将具有重要的临床转化意义，并且应该导致针对 PDAC 患者的新型联合疗法的开发。