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，5年生存率低于5%。PDAC的高死亡率主要是由于诊断时广泛的浸润和转移性疾病以及对化疗的普遍耐药。生物靶向治疗正在研究中，希望能提高PDAC患者的生存率。迄今为止，这些疗法提供了非常适度的生存期延长，而没有增加总生存期。目前，已知的引起PDAC的遗传改变与这些改变如何影响介导侵袭性和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说明了罗恩激酶和Smad非依赖性TGF 2信号之间的动态串扰的发现，促进肿瘤生长，侵袭和转移。此外，我们证明，罗恩不是异常表达的癌症干细胞群体，但在肿瘤进展过程中诱导的结果损失或衰减的Smad信号转导和通过转录激活，部分通过HIF-11。基于这些发现，我们假设TGF 2/罗恩轴在PDAC的进展中起重要作用，并且理解这些途径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目标：目标1。明确罗恩/TGF 2轴在PDAC发生发展中的功能作用。目标2.确定导致PDAC中罗恩异常上调的机制，以及罗恩是否在侵袭性但非癌症干细胞群体中差异表达。目标3.确定靶向罗恩/TGF β轴是否改善PDAC的治疗。本申请中提出的研究将研究TGF 2和罗恩激酶的相互作用在PDAC的侵袭性中所起的作用，前提是该知识将有助于新的治疗方法。拟定的研究将作为Audie Murphy VA医院临床试验和转化研究项目的一部分进行，PI James Freeman博士领导分子肿瘤学小组。本临床前研究的目的是为VA人群的临床试验提供基础，旨在改善患有PDAC的VA患者的生存率。该奖项将对退伍军人医疗保健的进一步影响是，该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VA系统中的医生科学家的候选人提供了一个很好的培训场所。 公共卫生相关性： 胰腺癌（PDAC）是VA患者人群中癌症死亡的第四大原因，中位生存率低于5%。PDAC对化疗和放疗具有高度抵抗性。目前的治疗包括抑制在肿瘤进展中起作用的异常表达的酶和途径。然而，在引起PDAC的已知遗传改变与这些改变如何影响介导侵袭性和对治疗的抗性的关键信号通路之间存在差距。我们最近发现罗恩激酶和TGF-2的相互作用在PDAC的进展中起重要作用。本申请中提出的研究将调查罗恩激酶和TGF 2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。

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.