Targeting HMGA1 in Pancreatic Tumor Progression

描述（由申请人提供）：胰腺导管腺癌（PDA）是一种高致死性恶性肿瘤，每年在全世界造成超过160，000例死亡。大多数患者患有无法手术的转移性疾病，对此没有有效的治疗方法。因此，迫切需要研究以确定PDA如何进展，以便设计更合理的靶向治疗。我们正在研究导致PDA肿瘤进展的分子途径。我们的重点是HMGA 1癌基因，它编码HMGA 1a和HMGA 1b蛋白亚型。这些染色质结合蛋白在调节基因表达中起作用。我们的初步研究表明，HMGA 1在人PDA中过表达，在侵袭性、转移性肿瘤中高水平表达，但在正常胰腺或早期前驱病变中不表达。我们还发现，HMGA 1a与激活的RAS癌基因合作，并在来自正常胰腺组织的培养人胰腺细胞中赋予转化表型。具体而言，经工程改造以过表达活化RAS和HMGA 1a的细胞在软琼脂中形成病灶，并在裸鼠中形成肿瘤。抑制HMGA 1在转移性人PDA细胞中的功能可阻断体外转化表型和体内PDA原位小鼠模型中的转移。这些发现表明HMGA 1促进PDA中的肿瘤进展。我们还发现HMGA 1在某些肿瘤中上调环氧化酶-2（考克斯-2）基因。考克斯-2基因在人类癌症中高度表达，包括PDA，并且被认为有助于肿瘤发生。我们的初步研究结果表明，高水平的考克斯-2蛋白在PDA与HMGA 1的高表达。在临床前的初步研究中，我们还发现考克斯-2抑制剂可以阻断移植人PDA的裸鼠的肿瘤发生。基于这些发现，我们假设HMGA 1-考克斯-2通路促进PDA中的肿瘤进展。使用我们独特的实验试剂，我们现在提出用以下具体目标来检验我们的假设：1。确定HMGA 1a和考克斯-2蛋白水平是否与PDA中更晚期疾病相关，2.）确定考克斯-2是否是PDA中HMGA 1的下游靶标，以及3.）在我们的实验模型中，确定靶向HMGA 1-考克斯-2通路是否能有效阻断PDA肿瘤进展。这些研究的结果将增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：目前迫切需要进行研究，以确定胰腺癌的合理治疗方法，因为几乎所有患有这种癌症的患者都死于疾病进展。仅今年，美国就有超过30，000人死于胰腺癌，全球死亡人数超过160，000人。在这项资助中，我们提出了研究，以确定在胰腺癌的发展中重要的细胞通路，重点是那些可以在治疗中靶向。

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.