Targeting MNK Pathways in Pancreatic Cancer

胰腺导管腺癌（PDAC）的死亡率很低，这是因为它是一种恶性肿瘤。 高度耐药性和侵袭性癌症。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 富含胶原的基质可以介导上皮-间质转化（EMT） 并促进癌细胞的侵袭。PDAC肿瘤也与mRNA表达失调有关。 翻译.我们已经提供了证据，3D胶原蛋白中的PDAC细胞激活MNK激酶介导 eIF 4E磷酸化并调节EMT调节因子的mRNA翻译。长期目标是为 致力于开发用于治疗PDAC的新的基于机制的靶向疗法。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， vivo.中心假设是靶向MNK激酶将减少PDAC肿瘤生长和转移 抑制CSC的数量第二个假设是靶向MNK激酶将导致重塑 以及PDAC肿瘤中基质的正常化。这些假设是基于大量的初步数据 这表明MNK抑制剂降低了3D胶原中的侵袭，抑制了人PDAC的生长， 类器官，减少EMT激活剂ZEB 1和Snail的mRNA翻译，减少CSC群体， 并减少星状细胞的胶原蛋白产生。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的PDAC进展中的作用; 2）评估MNK激酶在PDAC进展中的作用。 调节胰腺CSC;和3）确定MNK激酶在调节胰腺CSC中的基质反应中的作用。 vivo.在第一个目标下，MNK 1和MNK 2对人PDAC中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情况。它们在增强mRNA中的作用 将评估EMT调节因子和其他促肿瘤发生MNK靶基因的翻译。第二 本研究旨在评估MNK激酶靶向对胰腺CSCs的作用， 体外和体内测定，以及MNK 1和MNK 2对CSC调节的各自贡献， CSC调控基因将被解剖。在第三个目标中，MNK抑制剂调节 测定星状细胞活化和胶原蛋白产生。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 该提案中的创新要素，包括识别可以针对 消除PDAC肿瘤中的CSC和使用胰腺癌复杂模型的独特组合， 包括体外类器官培养和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高度意义，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。

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.