Novel Suppressors of Pancreatic Cancer

描述（由申请方提供）：胰腺导管腺癌（PDAC）是一种高度侵袭性、致死性癌症，其特征为广泛的基因组不稳定性和非整倍性。PDAC的特征性改变之一是p14 ARF（替代阅读框架）肿瘤抑制因子的失活。研究表明，在50-75%的人类病例中，ARF-p53信号传导被破坏，并在基因工程小鼠疾病模型中抑制PDAC进展方面发挥关键作用。重要的是，ARF也独立于p53肿瘤抑制因子发挥作用以预防癌症。因此，在保留野生型ARF和p53的剩余25-50%的PDAC中，ARF的p53非依赖性信号传导的组分可能被破坏。我们最近发现了一种新的ARF伴侣（Parf），它是在p53缺失的情况下ARF信号传导所必需的。Parf还独立于ARF发挥作用，以维持基因组稳定性并抑制多种细胞类型，特别是胰腺癌细胞系的增殖。与其他组织相比，Parf转录物和蛋白质在正常胰腺中表达最高，并且有证据表明其在人PDAC中失活。这些发现支持了Parf是一种新的肿瘤抑制基因的假设，该基因促进基因组稳定性并抑制胰腺癌的恶性进展。此外，由于Parf表现出与ARF以及其他抗癌途径交叉的抗癌活性，我们推测它可以在ARF阳性和ARF阴性肿瘤中靶向灭活。该提案使用分子方法和PDAC小鼠模型来测试这些想法。目的1将确定Parf的失活是否发生在表现出增加的染色体不稳定性的PDAC晚期。目的2使用新的小鼠模型来测试Parf是否正常地抑制PDAC在体内的发展和/或转移。这项工作将促进我们对PDAC分子基础的理解，并导致新的人类胰腺癌实验模型，从而促进PDAC的检测和治疗。这些目标直接涉及胰腺癌试点研究计划公告中定义的关键举措。公共卫生相关性：胰腺导管腺癌（PDAC）可以说是美国所有癌症中最致命的，因为缺乏早期发现和无效治疗。这项研究将促进我们对PDAC分子基础的理解，并为人类胰腺癌提供新的实验模型，从而促进改善对这种目前无法治愈和毁灭性疾病的检测和治疗。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, lethal cancer characterized by extensive genomic instability and aneuploidy. One of the signature alterations of PDAC is inactivation of the p14ARF (Alternative Reading Frame) tumor suppressor. It has been shown that ARF-p53 signaling is disrupted in 50-75% of human cases and plays a critical role in restraining PDAC progression in genetically engineered mouse models of the disease. Importantly, ARF also functions independent of the p53 tumor suppressor to prevent cancer. As such, components of ARF's p53-independent signaling may be disrupted in the remaining 25-50% of PDAC that retain wild type ARF and p53. We recently discovered a novel Partner of ARF (Parf) that is required for ARF signaling in the absence of p53. Parf also acts independent of ARF to maintain genomic stability and restrain the proliferation of multiple cell types, particularly pancreatic cancer lines. The Parf transcript and protein is most highly expressed in the normal pancreas compared to other tissues and there is evidence for its inactivation in human PDAC. These findings support the hypothesis that Parf is a novel tumor suppressor gene that promotes genomic stability and inhibits the malignant progression of pancreatic cancer. Moreover, because Parf exhibits anticancer activities that intersect with ARF as well as other anticancer pathways, we speculate it could be targeted for inactivation in both ARF-positive and ARF-negative tumors. This proposal tests these ideas using molecular approaches and mouse models of PDAC. Aim 1 will determine if inactivation of Parf occurs in advanced stages of PDAC that exhibit increased chromosomal instability. Aim 2 uses novel mouse models to test if Parf normally suppresses PDAC development and/or metastasis in vivo. This work will advance our understanding of the molecular basis of PDAC and result in new experimental models for human pancreatic cancer, thereby facilitating improved detection and treatment of PDAC. These goals directly address key initiatives defined in the program announcement for Pilot Studies in Pancreatic Cancer. PUBLIC HEALTH RELEVANCE: Pancreatic ductal adenocarcinoma (PDAC) is arguably the deadliest of all cancers in the United States due to lack of early detection and ineffective treatments. This study will advance our understanding of the molecular basis of PDAC and provide new experimental models for human pancreatic cancer, thereby facilitating improved detection and treatment of this currently incurable and devastating disease.