Role of Ron kinase in pancreatic cancer

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，其五年存活率不到5%。PDAC的高死亡率主要是由于诊断时广泛存在的侵袭性和转移性疾病以及对化疗的普遍抵抗所致。生物靶向治疗正在研究中，希望能提高PDAC患者的存活率。到目前为止，这些疗法在没有增加总存活率的情况下，提供了非常温和的生存时间的增加。目前，导致PDAC的已知基因改变与这些改变如何影响关键的信号通路和介导侵袭性和化疗耐药的网络之间存在差距。我们的初步数据详细说明了在RON激酶和Smad非依赖性TGF2信号之间发现的动态串扰，它促进了肿瘤的生长、侵袭和转移。此外，我们证明了RON在肿瘤干细胞群体中没有异常表达，但在肿瘤进展过程中由于Smad信号的丢失或减弱而被诱导，并部分通过HIF-11转录激活。基于这些发现，我们假设TGF2/RON轴在PDAC的进展中起着重要作用，了解这些通路的相互作用将导致改进治疗的新策略。为了验证这一假设，我们提出了三个具体的目标：目的1.确定RON/TGF2轴在PDAC发生发展中的功能作用。目的2.确定PDAC中RON异常上调的机制(S)，以及RON在侵袭性非肿瘤干细胞群体中是否存在差异表达。目的3.确定靶向RON/TGFb轴是否能改善PDAC的治疗。目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，前提是这一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翻译研究计划的一部分进行，该医院的PI詹姆斯·弗里曼博士领导分子肿瘤学小组。这项临床前研究的目的是为在VA人群中进行临床试验提供基础，目的是提高患有PDAC的VA患者的存活率。这一奖项将对退伍军人医疗保健产生进一步的影响，这一研究项目与医学肿瘤学奖学金计划相结合，因此为寻求成为退伍军人管理局内科科学家的候选人提供了一个极好的培训场所。

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.