Role of Ron kinase in pancreatic cancer

Ron 激酶在胰腺癌中的作用

• 批准号: 8043361
• 负责人: James W. Freeman
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043361
• 关键词: Address; Adenocarcinoma Cell; Affect; Attenuated; Award; Binding; Breast Cancer Cell; CD44 gene; Cancer Etiology; Cancer cell line; Cells; Cessation of life; Clinical Trials; DNA; Data; Development; Diagnosis; Disease; Epithelial Cells; Event; Fellowship Program; Functional disorder; Funding; Genes; Genetic; Genetic Transcription; Goals; Growth; HIF1A gene; Healthcare; Hospitals; Hypoxia; In Vitro; Investigation; Knock-out; Knowledge; Lead; Length; Lesion by Stage; Ligands; Link; Malignant neoplasm of pancreas; Mediating; Medical Oncology; Molecular Target; Mutation; Neoplasm Metastasis; Null Lymphocytes; Oncogenic; Oncology Group; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phosphotransferases; Physicians; Play; Population; Property; Radiation therapy; Regulator Genes; Reporting; Research Project Grants; Resistance; Role; Scientist; Signal Pathway; Signal Transduction; Solid Neoplasm; Survival Rate; System; Testing; Therapeutic; Time; Training; Transcription Coactivator; Transcriptional Activation; Transforming Growth Factor beta; Translational Research; Tumor Cell Invasion; Tumor Promoters; Tumor Suppressor Proteins; Tumor-Derived; Up-Regulation; Veterans; attenuation; base; cancer stem cell; cell growth; chemotherapy; enzyme pathway; gene repression; improved; in vivo; inhibitor/antagonist; kinase inhibitor; knock-down; molecular oncology; mortality; neoplastic cell; novel strategies; outcome forecast; patient population; preclinical study; prevent; programs; promoter; receptor; stem cell population; therapeutic target; therapy resistant; transcription factor; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinomas (PDAC) continue to have the worst prognosis of all solid tumors with a five-year survival of less than 5%. The high mortality rate from PDAC is mainly caused by widepread invasive and metastatic disease at the time of diagnosis and general resistance to chemotherapy. Biologically targeted therapies are under investigation with the hope of improving survival of patients with PDAC. To date these therapies provide very modest increase in survival length with no increase in overall survival. Currently gaps exist between known genetic alterations that give rise to PDAC with how these alterations impact critical signaling pathways and networks that mediate invasiveness and chemoresistance. Our preliminary data details the discovery of a dynamic cross talk between Ron kinase and Smad-independent TGF2 signaling that promotes tumor growth, invasion and metastasis. Moreover, we demonstrate that Ron is not aberrantly expressed in the cancer stem cell population but is induced during tumor progression as a result of loss or attenuation of Smad signaling and through transcriptional activation in part through HIF-11. Based on these findings we hypothesize that the TGF2/RON axis plays an important role in progression of PDAC and that understanding the interactions of these pathways will lead to novel strategies for improving therapy. To test this hypothesis we propose three specific aims: Objective 1. Determine the functional role of Ron/TGF2 axis in the development and progression of PDAC. Objective 2. Determine the mechanism(s) that causes aberrant up regulation of Ron in PDAC and whether Ron is differentially expressed in an invasive but non cancer stem cell population. Objective 3. Determine whether targeting the Ron/TGFb axis improves therapy of PDAC. The studies proposed in the current application will investigate the role that interaction of TGF2 and RON kinase play in the invasive properties of PDAC with the premise that this knowledge will contribute to new approaches for therapy. The proposed studies will be conducted as part of the clinical trials and translational research program at the Audie Murphy VA-Hospital for which the PI, Dr. James Freeman, directs the molecular oncology group. The goal of this pre-clinical study is to provide the bases for clinical trials in the VA population with the aim of improving survival of VA patients that present with PDAC. A further impact that this award will have on veterans health care is that this research project is integrated with the medical oncology fellowship program and therefore offers an excellent training venue for candidates seeking to become physician-scientist in the VA system. PUBLIC HEALTH RELEVANCE: Pancreatic cancer (PDAC) is the fourth leading cause of cancer deaths in the VA patient population with a median survival rate of less than 5%. PDAC are highly resistant to chemo- and radiation therapy. Present therapy includes inhibiting aberrantly expressed enzymes and pathways that play a role in tumor progression. However, gaps exist between known genetic alterations that give rise to PDAC with how these alterations impact critical signaling pathways that mediate invasiveness and resistance to therapy. We recently found that the interaction of Ron kinase and TGF2 play an important role in the progression of PDAC. Studies proposed in the current application will investigate the mechanisms by which Ron Kinase and TGF2 promote the invasion of PDAC. The knowledge gained from these studies will hopefully contribute to new approaches for therapy.

描述（由申请人提供）： 胰腺导管腺癌 (PDAC) 仍然是所有实体瘤中预后最差的，五年生存率低于 5%。 PDAC的高死亡率主要是由于诊断时广泛的侵袭性和转移性疾病以及对化疗的普遍耐药性造成的。生物靶向疗法正在研究中，希望能够提高 PDAC 患者的生存率。迄今为止，这些疗法仅略微延长了生存时间，但总体生存率没有增加。目前，导致 PDAC 的已知基因改变与这些改变如何影响介导侵袭性和化疗耐药性的关键信号通路和网络之间存在差距。我们的初步数据详细介绍了 Ron 激酶和不依赖于 Smad 的 TGF2 信号传导之间的动态串扰的发现，这种串扰可促进肿瘤生长、侵袭和转移。此外，我们证明 Ron 在癌症干细胞群中并没有异常表达，而是在肿瘤进展过程中由于 Smad 信号传导丢失或减弱以及部分通过 HIF-11 转录激活而被诱导。基于这些发现，我们假设 TGF2/RON 轴在 PDAC 的进展中发挥重要作用，并且了解这些途径的相互作用将导致改进治疗的新策略。为了检验这一假设，我们提出了三个具体目标： 目标 1. 确定 Ron/TGF2 轴在 PDAC 发生和进展中的功能作用。目标 2. 确定导致 PDAC 中 Ron 异常上调的机制以及 Ron 在侵袭性非癌症干细胞群中是否存在差异表达。目标 3. 确定靶向 Ron/TGFb 轴是否可以改善 PDAC 的治疗。当前申请中提出的研究将调查 TGF2 和 RON 激酶的相互作用在 PDAC 侵袭特性中所起的作用，前提是这些知识将有助于新的治疗方法。拟议的研究将作为奥迪墨菲退伍军人医院临床试验和转化研究计划的一部分进行，该医院的分子肿瘤学小组由首席研究员 James Freeman 博士领导。这项临床前研究的目的是为 VA 人群中的临床试验提供基础，旨在提高患有 PDAC 的 VA 患者的生存率。该奖项将对退伍军人医疗保健产生进一步的影响，因为该研究项目与医学肿瘤学研究金计划相结合，因此为寻求成为退伍军人管理局系统医师科学家的候选人提供了绝佳的培训场所。 公共卫生相关性： 胰腺癌 (PDAC) 是 VA 患者群体中第四大癌症死亡原因，中位生存率低于 5%。 PDAC 对化疗和放疗具有高度抵抗力。目前的治疗包括抑制在肿瘤进展中发挥作用的异常表达的酶和途径。然而，导致 PDAC 的已知基因改变与这些改变如何影响介导侵袭性和治疗耐药性的关键信号通路之间存在差距。我们最近发现Ron激酶和TGF2的相互作用在PDAC的进展中发挥重要作用。当前申请中提出的研究将调查 Ron 激酶和 TGF2 促进 PDAC 侵袭的机制。从这些研究中获得的知识有望有助于新的治疗方法。