Targeting MNK Pathways in Pancreatic Cancer

靶向胰腺癌中的 MNK 通路

• 批准号: 9898302
• 负责人: Hidayatullah G. Munshi
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898302
• 关键词: 3-Dimensional; Adenocarcinoma Cell; Attenuated; Biological Assay; Clinical Trials; Collagen; Complex; Data; Development; Effectiveness; Elements; Epithelial; Epithelium; Eukaryotic Initiation Factors; Future; Genes; Genetic Translation; Goals; Growth; Health; Human; In Vitro; Individual; Innovative Therapy; Literature; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Mesenchymal; Mission; Neoplasm Metastasis; Organoids; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Phosphorylation; Phosphotransferases; Population Decreases; Production; Property; Reaction; Regulation; Research; Resistance; Role; Signal Pathway; Snails; Testing; Transgenic Mice; Transgenic Model; Veterans; Work; base; cancer cell; cancer recurrence; cancer stem cell; chemotherapy; evidence base; expectation; improved; in vivo; inhibitor/antagonist; innovation; mortality; mouse model; novel; outcome forecast; pancreatic cancer model; stellate cell; stem cell population; targeted treatment; tumor; tumor growth; tumor progression; tumorigenic

The dismal mortality rate for pancreatic ductal adenocarcinoma (PDAC) is attributed to the fact that it is a highly chemo-resistant and aggressive cancer. Current therapies have also not been able to eradicate cancer stem cells (CSCs), which can reestablish tumors following treatment. Notably, PDAC tumors are associated with intensely collagen-rich stroma that we have shown can mediate epithelial-mesenchymal transition (EMT) and contribute to cancer cell invasion. PDAC tumors are also associated with dys-regulation of mRNA translation. We have provided evidence that PDAC cells in 3D collagen activate MNK kinases to mediate eIF4E phosphorylation and regulate mRNA translation of EMT regulators. The long-term goal is to contribute toward the development of novel mechanism-based targeted therapies for the treatment of PDAC. The main objective in this application is to determine how MNK kinases mediate tumor development and progression in vivo. The central hypothesis is that targeting MNK kinases will decrease PDAC tumor growth and metastasis and suppress the CSC population. A second hypothesis is that targeting MNK kinases will lead to remodeling and normalization of the stroma in PDAC tumors. These hypotheses are based on extensive preliminary data demonstrating that MNK inhibitors decrease invasion in 3D collagen, suppress growth of human PDAC organoids, decrease mRNA translation of the EMT activators ZEB1 and Snail, decrease the CSC population, and decrease collagen production by stellate cells. Three specific aims are proposed: 1) Determine the role of MNK kinases in PDAC progression in organoid and mouse models; 2) Evaluate the role of MNK kinases in regulating pancreatic CSCs; and 3) Determine the role of MNK kinases in regulating the stromal reaction in vivo. Under the first aim, the relative contribution of MNK1 and MNK2 to tumor progression in human PDAC organoids, and in orthotopic and transgenic mouse models, will be determined. Their roles in enhancing mRNA translation of EMT regulators and other pro-tumorigenic MNK target genes will be evaluated. For the second aim, studies will be performed to evaluate the effects of MNK kinase targeting on pancreatic CSCs using in vitro and in vivo assays, and the individual contributions of MNK1 and MNK2 to the regulation of CSCs and CSC-regulating genes will be dissected. In the third aim, the mechanism by which MNK inhibitors regulate stellate cell activation and collagen production will be determined. In addition, the ability of MNK inhibitors to remodel and normalize the fibrotic stroma in mouse models will also be evaluated. There are several innovative elements in this proposal, including the identification of signaling pathways that can be targeted to eliminate CSCs in PDAC tumors and the use of a unique combination of complex models of pancreatic cancer, including in vitro organoid cultures and in vivo orthotopic and transgenic models, to delineate the role of MNK kinases in PDAC progression. We anticipate that the results of this work will be of high significance, as they will provide scientific justification for the development and future clinical trials of MNK inhibitors in PDAC.

胰腺导管腺癌 (PDAC) 的死亡率很低，原因在于它是一种 高度化疗耐药和侵袭性癌症。目前的疗法也无法根除癌症 干细胞（CSC），可以在治疗后重建肿瘤。值得注意的是，PDAC 肿瘤与 我们已证明富含胶原蛋白的基质可以介导上皮间质转化 (EMT) 并有助于癌细胞的侵袭。 PDAC 肿瘤也与 mRNA 失调有关 翻译。我们提供的证据表明 3D 胶原蛋白中的 PDAC 细胞激活 MNK 激酶以介导 eIF4E 磷酸化并调节 EMT 调节因子的 mRNA 翻译。长期目标是做出贡献 致力于开发新的基于机制的靶向疗法来治疗 PDAC。主要 本申请的目的是确定 MNK 激酶如何介导肿瘤的发生和进展 体内。中心假设是靶向 MNK 激酶将减少 PDAC 肿瘤的生长和转移 并抑制 CSC 群体。第二个假设是，靶向 MNK 激酶将导致重塑 以及 PDAC 肿瘤基质的正常化。这些假设基于广泛的初步数据 证明 MNK 抑制剂可减少 3D 胶原蛋白的侵袭，抑制人 PDAC 的生长 类器官，减少 EMT 激活剂 ZEB1 和 Snail 的 mRNA 翻译，减少 CSC 数量， 并减少星状细胞产生的胶原蛋白。提出了三个具体目标： 1) 确定 MNK 激酶在类器官和小鼠模型中 PDAC 进展中的作用； 2) 评估MNK激酶在 调节胰腺 CSC； 3) 确定 MNK 激酶在调节基质反应中的作用 体内。第一个目标是 MNK1 和 MNK2 对人类 PDAC 肿瘤进展的相对贡献 将确定类器官以及原位和转基因小鼠模型中的类器官。它们在增强 mRNA 方面的作用 将评估 EMT 调节因子和其他促肿瘤 MNK 靶基因的翻译。对于第二个 目的，将进行研究以评估 MNK 激酶靶向对胰腺 CSC 的影响，用于 体外和体内测定，以及 MNK1 和 MNK2 对 CSC 和 CSC 调节的个体贡献 CSC 调节基因将被解剖。第三个目标是MNK抑制剂调节的机制 星状细胞的活化和胶原蛋白的产生将被确定。此外，MNK 抑制剂的能力 还将评估小鼠模型中纤维化基质的重塑和正常化。有几个 该提案中的创新要素，包括确定可针对的信号通路 消除 PDAC 肿瘤中的 CSC 并使用胰腺癌复杂模型的独特组合， 包括体外类器官培养以及体内原位和转基因模型，以描述 MNK 的作用 PDAC 进展中的激酶。我们预计这项工作的结果将具有重要意义，因为它们将 为 PDAC 中 MNK 抑制剂的开发和未来临床试验提供科学依据。