Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, remains one of the leading causes of death. This is mainly due to the lack of relevant detection methods and therapeutic targets, as well as therapy resistance. Gemcitabine, the current first-line treatment, is effective only in limited percentage f patients and typically encounters the problem of resistance. In this proposal, we propose to address these issues by focusing on the eukaryotic translation initiation factor 5A (eIF5A), a candidate biomarker and a chemotherapeutic target we identified through our preliminary studies. Our data show that eIF5A and activated form of this protein is upregulated in the majority of PDAC patient tissues from the onset of the disease, and inhibition of eIF5A activity efficiently kills PDAC cells in vitro. We also provide evidence that eIF5A regulates the expression of PEAK1 (pseudopodium atypical enriched kinase 1), a catalytically active kinase that we recently demonstrated as a signaling hub in PDAC cells critical for their survival and therapy resistance. Importantly, our data suggest that eIF5A hypusination and PEAK1 expression may constitute a compensatory mechanism responsible for resistance to gemcitabine. In this proposal, we propose to extensively study the mechanism of eIF5A regulation on PDAC growth and PEAK1 expression using both in vitro and in vivo models. First, using in vitro tissue culture models, we will determine how eIF5A regulates proliferation, cell cycle progression, apoptosis and tumorigenicity of PDAC cells and also determine whether PEAK1 is the downstream effector of eIF5A in PDAC growth. Subsequently, we will validate our in vitro results in vivo, using clinically relevant orthotopic implantation nude mouse models of pancreatic cancer. Completion of our studies will uncover a novel mechanism of PDAC growth and establish eIF5A as a novel therapeutic target, which will eventually address the need for a new, effective and feasible treatment for this deadly, difficult-to-treat disease.
Pancreatic ductal adenocarcinoma (PDAC) is the 4th most common cause of cancer-related death in the USA, with a survival rate of only 5%. Our proposed studies will test the importance of a unique biochemical signaling pathway in PDAC growth and metastasis. The obtained results will be of great importance in designing a novel therapeutic strategy targeting PDAC.
|Fujimura, Ken; Choi, Sunkyu; Wyse, Meghan et al. (2015) Eukaryotic Translation Initiation Factor 5A (EIF5A) Regulates Pancreatic Cancer Metastasis by Modulating RhoA and Rho-associated Kinase (ROCK) Protein Expression Levels. J Biol Chem 290:29907-19|
|Fujimura, Ken; Wright, Tracy; Strnadel, Jan et al. (2014) A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic cancer. Cancer Res 74:6671-81|