Pancreatic Ductal Adenocarcinoma (PDAC) remains remarkably lethal with a 5-year survival rate of less than 9%. Due to its widespread resistance to conventional therapy, PDAC is expected to be the second most common cause of cancer-related death in the United States by 2030. Oncogenic KRAS mutations are nearly uniform in PDAC, affecting over 90% of patients. The mutant KRAS is a key driver in the neoplastic phenotype, and leads to hyper-activation of KRAS, permitting for sustained proliferation, the evasion of apoptosis, as well as facilitating metastasis and the development of chemo-resistance. In spite of the importance of KRAS in PDAC pathobiology and extensive research aimed at the discovery of RAS-directed therapeutics, there are no FDA-approved drugs directed to target RAS; and RAS family proteins are largely considered `un-druggable'. Therefore, there is a need to identify either alternative- druggable target(s) or better approaches in hopes of improving patient outcomes. The inflammatory pathway is known to play significant roles in many cancer, including pancreatic cancer. Number of reports suggest that there is a direct link between inflammation and pancreatic cancer. We identified MLK3, a novel kinase that is activated by TNF? and plays role in pancreatic cancer pathogenesis. Recently we identified an MLK3 upstream kinase, MAP4K4, which is also activated by TNF?, suggesting perhaps, TNF?- MAP4K4-MLK3 axis might play a role in pancreatic cancer, which was corroborated by a recent report indicating worst outcomes in PDAC patient with high expression of MAP4K4. Considering our observation, we treated animal model of PDAC with a specific inhibitor of MAP4K4, GNE-495. Interestingly, the GNE-495 was able to ameliorate PDAC in the pre-clinical animal model, a significant decrease in stroma and increased cell death in cancerized ductal cells. Since immune cells play vital roles in cancer therapy, we examined peripheral immune compartment that had no effect of GNE-495. We rationalized to treat animals with 4-1BB agonistic antibody to activate effector T cells. The combined treatment of GNE-495 along with 4-1BB mab had profound effect on animal survival and almost stroma/Desmoplasia was absent in tumors. The overall objective of this proposal is to elucidate the role of MAP4K4 in PDAC and strategize a rational approach to combine MAP4K inhibitor and immunotherapies to overcome pancreatic cancer. The central objective will be addressed by: (1) defining the role of MAP4K4 in PDAC, (2) determining the impact of MAP4K4 inhibition in TME, and (3) determining impact of MAP4K inhibition along with immunotherapy on host immunity. Upon completion of these three aims, it is our expectation, that first, we will be able to establish the role of MAP4K4 in PDAC. Second, we would establish clinical significance of targeting MAP4K4, along with rationalized immunotherapy for an alternative pancreatic cancer treatment strategy.

Public Health Relevance

A number of reports suggest, high incidence of pancreatic cancer (PDAC) in ageing veterans with diabetes and veterans from Vietnam War. The PDAC is projected to be a second leading cause of cancer-related death in the United States by 2030 and currently being managed with chemotherapeutic agents such as Gemcitabine and nab-paclitaxel, which only modestly improve survival. Based on our results, we outline a series of experiments to investigate therapeutic efficacies of a kinase (MAP4K4) inhibitor along with immunotherapy for a better therapeutic option to manage PDAC in future.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (ZRD1)
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Jesse Brown VA Medical Center
United States
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