The prognosis for pancreatic cancer patients remains dismal. Effective therapy is clearly an unmet medical need for these patients. Aside from surgery which benefits a small fraction of patients, current standard treatment consists of strong chemotherapy that is highly toxic and with less than 50% chance of working. For those who initially benefit from chemotherapy, rapid progression is inevitable. The promise of immunotherapy, while already realized in other cancer types, has failed to show benefit for pancreatic cancer patients. Therapeutic breakthrough must therefore come from novel discoveries in the biology of pancreatic cancer. We now recently found, for the first time in literature, that pancreatic cancer cells ?armored? themselves by activating the innate immunity, a self-defense mechanism that is usually summoned when cells are injured or invaded by microorganisms. In doing so pancreatic cancer cells become highly aggressive and resistant to chemotherapeutics. Our approach is to ?deactivate? such defense mechanism in pancreatic cancer cells by inhibiting Interleukin-1 Receptor-Associated Kinase 4 (IRAK4), the master switch that controls the innate immune pathway. By doing so we found that pancreatic cancer cells become greatly weakened and are much more vulnerable to chemotherapy. On this premise we have now made further potentially impactful findings that we plan to confirm and pursue in the following three aims: 1.
Aim 1 : We found that presence of IRAK4 is essential for supporting transformed growth and cellular signaling driven by oncogenic KRAS, a genetic event that is present in almost all pancreatic cancer. We will explore the mechanistic detail and determine whether loss of IRAK4 will impede KRAS-driven pancreatic tumorigenesis using human pancreatic cancer cell lines and state-of-the-art genetic mouse models. If shown to be true, these results could have impact on other KRAS-mutant cancer types. 2.
Aim 2 : We have generated an IRAK4-deficient pancreatic cancer mouse model that we plan to characterize to understand the consequence of global IRAK4 loss, as will happen with pharmacologic inhibition, in pancreatic cancer progression. In addition, we will specifically study the role of immune IRAK4 in pancreatic cancer growth, which will yield clinically useful information if IRAK4 inhibitors are advanced into clinical trials in the future. 3.
Aim 3 : Our preliminary data shows that IRAK4 inhibition renders immunotherapy effective in genetic mouse model. In this aim we will test two novel, highly potent IRAK4 inhibitors, with the ultimate goal of translating these findings into clinical trials.

Public Health Relevance

This proposal aims at targeting a key regulatory switch of the innate immune pathway, the Interleukin-1 Receptor- Associated Kinase 4 (or IRAK4) as a novel therapeutic strategy in pancreatic cancer, based on recent findings from our lab. We will explore how signaling emanating from IRAK4 intersect with oncogenic KRAS signaling, investigate the global and immune-related role of IRAK4 in pancreatic cancer, and develop IRAK4 inhibitor- based immunotherapeutic regimen that can be translated into clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA219697-01A1
Application #
9521812
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Chen, Weiwei
Project Start
2018-02-08
Project End
2023-01-31
Budget Start
2018-02-08
Budget End
2019-01-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130