The Role of Cyr61 in Patho-Biology and Therapeutics of Pancreatic Cancer

描述(由申请人提供)： 背景和理论：胰腺导管腺癌(PDAC)是美国癌症死亡的第四大原因，预后极其糟糕。目前还没有有效甚至姑息治疗PDAC的方法，目前的治疗方法并没有减少肿瘤的发病或改善患者的生存。他们对许多化疗疗法和目前的标准护理疗法，如吉西他滨(Gem)表现出极强的抵抗力。因此，需要对PDAC进展的病因学及其耐药的确切机制有新的认识。Cyr61(富含半胱氨酸的61)是一种与肝素结合的富含半胱氨酸的分泌型蛋白，由生长因子诱导基因编码，在胰腺癌细胞和前驱病变中经常升高。我们的初步研究发现，Cyr61在胰腺癌的发生和耐药中起积极作用。它调节Sonic Hedgehog(Shh)的表达，Sonic Hedgehog(Shh)与PDAC的维持、进展和Gem抗性广泛相关。然而，Cyr61发挥压倒性作用的机制(S)仍然难以捉摸。假设：根据我们的初步研究结果，我们假设Cyr61是Shh信号的关键上游正调控因子，正是通过Shh信号，Cyr61调控胰腺癌的生长和进展。这些数据使我们进一步假设，在化疗耐药的环境中阻断Cyr61信号比在一线治疗中抑制通路更有效。具体目的：本应用的具体目的是：(1)确定Cyr61调控胰腺癌细胞Shh表达及其下游介导物的分子机制；(2)阐明Cyr61调控胰腺癌细胞生长和侵袭表型的机制；(3)通过体外和原位异种移植瘤模型，探讨Cyr61在增强PDAC细胞化疗耐药性中的作用。Shh的参与将被调查。意义：这三个目标的完成将为Cyr61作为胰腺癌治疗的新分子靶点提供一个机制特征。因此，拟议的研究有可能对胰腺癌患者的临床治疗产生影响。 公共卫生相关性： 胰腺导管腺癌(PDAC)是美国第四大癌症死亡原因。PDAC患者的存活率是实体肿瘤中最差的，这是由于其发现晚、转移早以及对常规化疗耐药的原因。我们认为Cyr61可能是PDAC的早期和晚期调节因子。这一见解是从我们最近的发现发展起来的，这些发现表明Cyr61调节Sonic Hedgehog(Shh)的表达。Cyr61促进与疾病进展和化疗耐药相关的多个关键事件。本项目的目的是评估Cyr61在胰腺癌中调控Shh表达的机制，以及揭示Cyr61促进肿瘤进展和远处器官转移生长的机制。此外，还将评估Cyr61在化疗耐药中的作用。我们预计，这些研究的结果将表明，靶向Cyr61可以为胰腺癌患者提供一种新的治疗选择。

DESCRIPTION (provided by applicant): Background and Rationale: Pancreatic ductal adenocarcinoma (PDAC), which is the fourth leading cause of cancer deaths in the United States, carries an extremely dismal prognosis. There are currently no effective or even palliative therapies for PDAC, and present approaches have not reduced tumor pathogenesis or improved patient survival. They exhibit profound resistance to many chemotherapeutic treatments and the current standard-of-care therapies, such as Gemcitabine (Gem). Therefore, new insights into the etiology of PDAC progression along with its precise mechanisms of drug resistance need to be discovered. Cyr61 (Cysteine rich 61), a heparin-binding, cysteine-rich, secreted protein encoded by a growth factor-inducible gene, is frequently elevated in pancreatic cancer cells and in precursor lesions. Our preliminary studies found that Cyr61 plays a positive role in pancreatic carcinogenesis and drug resistance. It regulates the expression of Sonic Hedgehog (SHh), which is widely linked to the maintenance, progression and Gem resistance of PDAC. However, the mechanism(s) by which Cyr61 exerts its overwhelming actions remains elusive. Hypothesis: Guided by the results of our preliminary studies, we hypothesize that Cyr61 is a key upstream positive regulator of SHh signaling, and it is through the SHh signaling that Cyr61 modulates pancreatic cancer growth and progression. The data lead us to further hypothesize that blocking Cyr61 signaling in a chemo- resistant setting is more effective than inhibiting the pathways in the first line treatment. Specific Aims: The specific aims of this application are to: (1) determine the molecular mechanisms through which Cyr61 regulates SHh expression and its down-stream mediators in pancreatic cancer cells, (2) elucidate the mechanisms whereby Cyr61 regulates the tumor growth and invasive phenotypes of pancreatic cancer cells and (3) explore the role of Cyr61 in enhancing chemoresistance of PDAC cells using both in vitro and orthotopic xenograft tumor models. The involvement of SHh will be investigated. Significance: Completion of these three aims will provide a mechanistic characterization of Cyr61 as a novel molecular target for pancreatic cancer therapy. Therefore, the proposed studies have the potential to impact the clinical treatment of pancreatic cancer patients. PUBLIC HEALTH RELEVANCE: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the United States. A patient with PDAC has the worst survival rate of any solid tumor due to its late detection, early metastasis, and resistance to conventional chemotherapy. We have suggested that Cyr61 may be an early and late mediator of PDAC. This insight is developed from our recent findings which indicate that Cyr61 regulates Sonic Hedgehog (SHh) expression. Cyr61 promotes multiple crucial events associated with the progression of the disease and resistance to chemotherapy. The objectives of this project are to evaluate the mechanism whereby Cyr61 regulates SHh expression in pancreatic cancer, as well as uncover the mechanisms by which Cyr61 promotes tumor progression and metastatic growth to the distant organs. The role of Cyr61 in resistance to chemotherapy will also be evaluated. We are anticipating that the outcome of these studies will propose that targeting Cyr61 can provide a new treatment option for patients with pancreatic cancer.