Deciphering the Role of eIF5A/PEAK1 Pathway in Pancreatic Cancer

描述(申请人提供)：胰腺导管腺癌(PDAC)，胰腺癌最常见的形式，仍然是主要的死亡原因之一。这主要是由于缺乏相关的检测方法和治疗靶点，以及治疗耐药性。吉西他滨是目前的一线治疗方法，仅对有限比例的患者有效，通常会遇到耐药性问题。在这个提案中，我们建议通过关注真核细胞翻译起始因子5A(EIF5A)来解决这些问题，eIF5A是我们通过初步研究确定的候选生物标志物和化疗靶点。我们的数据显示，从疾病开始，eIF5A及其激活形式在大多数PDAC患者组织中上调，抑制eIF5A活性在体外有效地杀死PDAC细胞。我们还提供了证据，eIF5A调节PEAK1(伪足非典型富集激酶1)的表达，PEAK1是一种催化活性的激酶，我们最近证明它是PDAC细胞中的一个信号枢纽，对其生存和治疗耐药至关重要。重要的是，我们的数据表明，eIF5A的过度激活和PEAK1的表达可能构成了对吉西他滨耐药的代偿机制。在这项建议中，我们建议通过体外和体内模型广泛研究eIF5A对PDAC生长和PEAK1表达的调控机制。首先，利用体外组织培养模型，我们将确定eIF5A如何调控PDAC细胞的增殖、细胞周期进展、凋亡和致瘤性，并确定PEAK1是否为PDAC生长中eIF5A的下游效应因子。随后，我们将使用临床相关的胰腺癌原位移植裸鼠模型，在体内验证我们的体外结果。我们研究的完成将揭示PDAC生长的新机制，并将eIF5A确立为新的治疗靶点，最终将满足对这种致命、难以治疗的疾病的新的、有效和可行的治疗方法的需求。

DESCRIPTION (provided by applicant): 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.