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

• 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
• 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

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.

现在，越来越多的研究表明，靶向溴生群和末端的抑制剂 介导mRNA转录的结构域（BET）蛋白具有抗肿瘤作用对胰腺导管 腺癌（PDAC）。 BET抑制剂还可以通过抑制激活的激活来使PDAC基质正常化 癌症相关的成纤维细胞（CAF）。但是，BET抑制剂诱导Rac1介导的MNK激活 激酶，介导mRNA翻译。重要的是，靶向MNK激酶和MNK效应子HNRNPA1 增强了BET抑制剂的功效。值得注意的是，MNK抑制剂会诱导CD8+ T细胞浸润，但它们 肿瘤相关巨噬细胞（TAM）抑制效应子功能。值得注意的是，BET抑制剂可以 减少TAM的渗透。本应用的目的是阐明 BET和MNK抑制剂的组合表明对PDAC的抗肿瘤反应。中央 假设是该组合有效地靶向癌细胞，调节肿瘤免疫 微环境，并将胰腺基质归一化以抑制PDAC生长。三个具体目标是 提议：1）定义和靶向负反馈回路，以增强BET抑制剂在 体内2）评估BET和MNK抑制剂对CD8+ T细胞浸润和 激活; 3）确定BET和MNK抑制剂对胰腺基质的组合的影响。 在第一个目标下，MNK效应子hnrnpa1和cyfip1的机制可以起作用 Rac1的下游，将评估限制BET抑制剂的功效。此外，共同治疗的功效 使用BET和MNK抑制剂将在PDAC的类器官和转基因小鼠模型中进行评估。为了 第二个目的，联合疗法对CD8+ T细胞浸润和激活和巨噬细胞的影响 将评估丰度和极化。另外，MNK激酶和MNK效应子的贡献 将评估巨噬细胞中HNRNPA1和CYFIP1限制BET抑制剂的功效。在第三 目的，将在转基因小鼠中表征组合疗法对基质反应的影响 模型。 MNK激酶，CYFIP1和HNRNPA1在胰腺CAF中的贡献对限制了限制的功效 还将评估BET抑制剂。另外，BET和MNK激酶活性，MNK之间的关系 效应子和基质反应将在人PDAC肿瘤标本中进行评估。有一些创新的 该提案中的元素，包括增强PDAC中抗肿瘤反应的新型治疗方法 患者;关于BET和MNK抑制剂的联合疗法如何调节肿瘤的新颖概念 免疫微环境和协同抗肿瘤反应的基质反应；和独特 PDAC复杂模型的组合，包括体内原位，器官和转基因小鼠模型。 这项拟议的研究很重要，因为它将具有重要的临床翻译意义，应 导致PDAC患者的新型组合疗法的发展。