Targeting HMGA1 in Pancreatic Tumor Progression

描述(申请人提供)：胰腺导管腺癌(PDA)是一种高度致命的恶性肿瘤，每年在全球范围内造成超过16万人死亡。大多数患者患有无法手术的转移性疾病，目前还没有有效的治疗方法。因此，迫切需要研究以确定PDA的进展情况，以便设计更合理、更有针对性的治疗方法。我们正在研究导致PDA肿瘤进展的分子途径。我们的重点是HMGA1癌基因，它编码HMGA1a和HMGA1b蛋白亚型。这些染色质结合蛋白具有调节基因表达的功能。我们的初步研究表明，HMGA1在人PDA中高表达，在侵袭性、转移性肿瘤中高表达，但在正常胰腺或早期前驱病变中不表达。我们还发现HMGA1a与激活的RAS癌基因协同作用，并在来源于正常胰腺组织的培养的人胰腺细胞中赋予转化表型。具体地说，被设计成过表达激活的RAS和HMGA1a的细胞在软琼脂中形成焦点，在裸鼠体内形成肿瘤。在转移的人PDA细胞中抑制HMGA1功能，在体外阻止转化的表型，并在体内阻止PDA的原位小鼠模型的转移。这些发现表明，HMGA1促进了PDA的肿瘤进展。我们还发现，在一些肿瘤中，HMGA1上调了环氧合酶-2(COX-2)基因。COX-2基因在包括PDA在内的人类癌症中高度表达，被认为与肿瘤的发生有关。我们的初步结果显示，在高表达HMGA1的PDA中，COX-2蛋白水平高。在一项临床前的先导性研究中，我们还发现COX-2抑制剂阻止了人PDA异种移植裸鼠的肿瘤形成。基于这些发现，我们假设HMGA1-COX-2通路促进了PDA的肿瘤进展。使用我们独特的实验试剂，我们现在建议验证我们的假设，具体目的如下：1)确定HMGA1a和COX-2蛋白水平是否与PDA中更晚期的疾病相关。确定COX-2是否为PDA中HMGA1的下游目标，以及，3.)在我们的实验模型中，确定靶向HMGA1-COX-2通路是否在阻止PDA肿瘤进展方面有效。这些研究的结果将加强我们对导致胰腺癌进展的分子途径的理解，并使我们能够开发更好的治疗方法。公共卫生相关性：迫切需要研究确定合理的胰腺癌治疗方法，因为几乎所有胰腺癌患者都死于疾病进展。仅今年一年，美国就有超过3万人死于胰腺癌，全球将有超过16万人死亡。在这笔拨款中，我们建议进行研究，以确定在胰腺癌发展中重要的细胞途径，重点是那些可以作为治疗靶点的途径。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinomas (PDA) are highly lethal malignancies accounting for over 160,000 deaths worldwide each year. Most patients present with inoperable, metastatic disease for which there are no effective therapies. Thus, research is urgently needed to determine how PDAs progress in order to design more rational, targeted therapy. We are studying the molecular pathways that lead to tumor progression in PDA. Our focus is the HMGA1 oncogene, which encodes the HMGA1a and HMGA1b protein isoforms. These chromatin binding proteins function in regulating gene expression. Our preliminary studies show that HMGA1 is overexpressed in human PDA, with high levels in invasive, metastatic tumors, but no expression in normal pancreas or early precursor lesions. We also discovered that HMGA1a cooperates with the activated RAS oncogene and confers a transformed phenotype in cultured human pancreatic cells derived from normal pancreatic tissue. Specifically, cells engineered to overexpress activated RAS and HMGA1a form foci in soft agar and tumors in nude mice. Inhibiting HMGA1 function in metastatic, human PDA cells blocks the transformed phenotype in vitro and metastases in an orthotopic mouse model for PDA in vivo. These findings suggest that HMGA1 promotes tumor progression in PDA. We also showed that HMGA1 up-regulates the cyclo-oxygenase-2 (COX-2) gene in some tumors. The COX-2 gene is highly expressed in human cancers, including PDAs, and is thought to contribute to tumorigenesis. Our preliminary results show high levels of COX-2 protein in PDAs with high expression of HMGA1. In a preclinical pilot study, we also found that COX-2 inhibitors block tumorigenesis in nude mice with human PDA xenografts. Based on these findings, we hypothesize that the HMGA1-COX-2 pathway promotes tumor progression in PDA. Using our unique experimental reagents, we now propose to test our hypothesis with the following Specific Aims: 1.) Determine if HMGA1a and COX-2 protein levels correlate with more advanced disease in PDA, 2.) Determine if COX-2 is a downstream target of HMGA1 in PDA, and, 3.) Determine if targeting the HMGA1-COX-2 pathway is effective in blocking PDA tumor progression in our experimental models. Results from these studies will enhance our understanding of the molecular pathways that lead to pancreatic cancer progression and should enable us to develop better therapies. PUBLIC HEALTH RELEVANCE: There is a dire need for research to identify rational therapies for pancreatic cancer because virtually all patients with this cancer die from disease progression. This year alone, over 30,000 people in the U.S. will succumb to pancreatic cancer with over 160,000 deaths worldwide. In this grant, we propose studies to identify cellular pathways important in the development of pancreatic cancer with emphasis on those that could be targeted in therapy.