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.
The proposed research is relevant to health of veterans and the VA's mission because characterizing the mechanisms that mediate pancreatic cancer development and progression is ultimately expected to help identify novel targets and approaches for the treatment of this highly lethal malignancy.
|Pham, Thao N; Kumar, Krishan; DeCant, Brian T et al. (2018) Induction of MNK kinases-dependent eIF4E phosphorylation by inhibitors targeting BET proteins limits efficacy of BET inhibitors. Mol Cancer Ther :|
|Ebine, Kazumi; Kumar, Krishan; Pham, Thao N et al. (2018) Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells. Sci Rep 8:13225|