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

Cyr61 在胰腺癌病理生物学和治疗中的作用

• 批准号: 8242631
• 负责人: SNIGDHA BANERJEE
• 金额: --
• 依托单位: KANSAS CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242631
• 关键词: Adenocarcinoma Cell; Alkaloids; Animals; Biology; Cancer Etiology; Cancer Patient; Caring; Cell Line; Cells; Cessation of life; Clinical Treatment; Culture Setup; Cysteine; Data; Diagnosis; Disease; Disease Resistance; Distant; Drug resistance; Early Diagnosis; Erinaceidae; Etiology; Event; Exhibits; Genes; Genetically Engineered Mouse; Growth; Growth Factor; Heparin Binding; Human; In Vitro; Integrins; Knowledge; Laboratories; Lead; Lesion; Ligands; Link; Longevity; Maintenance; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Target; Neoplasm Metastasis; Organ; Outcome Study; Palliative Care; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiologic Neovascularization; Play; Pre-Clinical Model; Proteins; Regulation; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Solid Neoplasm; Sonic Hedgehog Pathway; Stem cells; Stream; Survival Rate; Systemic Therapy; Teratogens; Testing; Therapeutic; Time; Translating; United States; Up-Regulation; Work; Xenograft Model; Xenograft procedure; cancer stem cell; cancer therapy; carcinogenesis; cell motility; chemotherapy; clinical practice; cyclopamine; epithelial to mesenchymal transition; gemcitabine; human SMO protein; improved; in vivo; inhibitor/antagonist; insight; migration; mouse model; notch protein; novel; outcome forecast; pancreatic cancer cells; prevent; public health relevance; receptor; research study; response; small molecule; smoothened signaling pathway; tissue culture; tumor; tumor growth; tumor progression; tumor xenograft

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.

描述（由申请人提供）： 背景和基本原理：胰腺导管腺癌 (PDAC) 是美国癌症死亡的第四大原因，其预后极为悲观。目前还没有针对 PDAC 的有效疗法，甚至没有姑息疗法，并且目前的方法并未减少肿瘤发病机制或提高患者生存率。它们对许多化疗方法和当前的标准护理疗法（例如吉西他滨（Gem））表现出强烈的抵抗力。因此，需要发现对 PDAC 进展的病因学及其精确的耐药机制的新见解。 Cyr61（富含半胱氨酸 61）是一种由生长因子诱导基因编码的肝素结合、富含半胱氨酸的分泌蛋白，在胰腺癌细胞和癌前病变中经常升高。我们的初步研究发现Cyr61在胰腺癌发生和耐药性中发挥积极作用。它调节 Sonic Hedgehog (SHh) 的表达，该表达与 PDAC 的维持、进展和 Gem 抗性广泛相关。然而，Cyr61 发挥其压倒性作用的机制仍然难以捉摸。假设：根据我们的初步研究结果，我们假设 Cyr61 是 SHh 信号传导的关键上游正调节因子，Cyr61 通过 SHh 信号传导调节胰腺癌的生长和进展。这些数据使我们进一步假设，在耐药环境中阻断 Cyr61 信号传导比在一线治疗中抑制通路更有效。具体目的：本申请的具体目的是：（1）确定Cyr61调节胰腺癌细胞中SHh表达及其下游介质的分子机制，（2）阐明Cyr61调节肿瘤生长和侵袭的机制。 (3) 使用体外和原位异种移植肿瘤模型探索 Cyr61 在增强 PDAC 细胞化疗耐药性中的作用。 SHh 的参与将受到调查。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机制表征。因此，拟议的研究有可能影响胰腺癌患者的临床治疗。 公共卫生相关性： 胰腺导管腺癌（PDAC）是美国癌症死亡的第四大原因。由于发现较晚、转移较早且对传统化疗产生耐药性，PDAC 患者的生存率是所有实体瘤中最低的。我们认为 Cyr61 可能是 PDAC 的早期和晚期介导者。这一见解是根据我们最近的发现得出的，该发现表明 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。该项目的目标是评估 Cyr61 调节胰腺癌中 SHh 表达的机制，并揭示 Cyr61 促进肿瘤进展和远处器官转移生长的机制。 Cyr61 在化疗耐药中的作用也将得到评估。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新的治疗选择。