Role of Ron kinase in pancreatic cancer

Ron 激酶在胰腺癌中的作用

• 批准号: 8696795
• 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/8696795
• 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.

描述（由申请人提供）： 胰腺导管腺癌（PDAC）在所有实体瘤中的预后仍然最差，五年生存率低于5％。 PDAC的高死亡率主要是由诊断时广泛的侵入性和转移性疾病引起的，并且对化学疗法的普遍抵抗。正在研究以生物学靶向疗法的疗法，希望改善PDAC患者的存活率。迄今为止，这些疗法可提供非常适中的生存长度增加，而总体生存期无增加。当前，在已知的遗传变量之间存在差距，这些遗传改变引起PDAC，这些变化如何影响介导侵入性和化学耐药性的关键信号通路和网络。我们的初步数据详细介绍了RON激酶与SMAD独立的TGF2信号传导之间的动态串扰，该发现促进了肿瘤的生长，侵袭和转移。此外，我们证明了罗恩在癌症干细胞种群中并未异常表达，而是由于SMAD信号传导的丧失或衰减而在肿瘤进展过程中诱导的，并且通过HIF-11进行了转录激活。根据这些发现，我们假设TGF2/RON轴在PDAC的进展中起着重要作用，并且了解这些途径的相互作用将导致改善治疗的新策略。为了检验该假设，我们提出了三个具体目标：目标1。确定RON/TGF2轴在PDAC的发展和进展中的功能作用。目标2。确定导致PDAC中RON异常调节的机制，以及在侵袭性但非癌症干细胞种群中RON是否差异表达。目标3。确定靶向RON/TGFB轴是否可以改善PDAC的治疗。当前应用中提出的研究将调查TGF2和RON激酶在PDAC的侵入性特性中的相互作用的作用，前提是这种知识将有助于新的治疗方法。拟议的研究将作为Audie Murphy VA - 医院的临床试验和转化研究计划的一部分进行，PI詹姆斯·弗里曼（James Freeman）博士指导了分子肿瘤学组。这项临床前研究的目的是为VA人群提供临床试验的基础，以改善PDAC存在的VA患者的生存率。该奖项将对退伍军人卫生保健产生的进一步影响是，该研究项目与医学肿瘤学奖学金计划融为一体，因此为寻求成为VA系统的医师科学家的候选人提供了出色的培训场地。