Stat3 Signaling in Pancreas Cancer

描述(由申请人提供)：胰腺导管腺癌(PDAC)迫切需要新的治疗策略。这项建议的长期目标是通过靶向PDAC肿瘤发生和内在耐药的关键介质来制定持久癌症缓解的策略。我们的中心假设是，致癌STAT3通路的激活代表(A)参与内在耐药，(B)构成PDAC的潜在治疗靶点。总体目标是了解STAT3在PDAC中结构性激活的机制，并确定其下游生物学效应和临床相关性。我们将利用功能获得和功能丧失的方法，通过定义关键的靶基因和建立STAT3、EGFR和Src激酶之间的功能相互作用来描述STAT3在PDAC肿瘤发生中的作用的分子机制。我们将利用PDAC的原位小鼠模型建立STAT3抑制的体内效应，并利用新的成像方法确定TME内STAT3信号相互作用的机制，以评估体内肿瘤血管生成、血流、缺氧和肿瘤药物输送。这将通过以下具体目标来实现：目的1：研究结构性激活的STAT3在PDAC的发病机制和内在耐药中的功能作用。假设：STAT3转录网络在PDAC的发病机制和化疗耐药中起关键作用。目的1a阐明PDAC中STAT3信号的结构性激活机制。目的1b将确定STAT3抑制和沉默对基本靶基因的生物学效应。目的1c将确定抑制和沉默STAT3是否能克服PDAC的耐药性。目的在一项全国性的临床试验中，确定活化的STAT3在接受吉西他滨和厄洛替尼治疗的PDAC患者中的预后意义。目的：探讨EGFR、Src和吉西他滨与STAT3相互作用在克服PDAC化疗耐药中的作用。假设：联合靶向治疗和STAT3将克服与STAT3介导的PDAC化疗耐药相关的多余信号通路和反馈环。目的：探讨PDAC中STAT3信号与肿瘤微环境的相互作用机制。肿瘤微环境(TME)在PDAC中起着至关重要的作用。假设：抑制STAT3将促进“血管正常化”和基质的耗尽，从而增强药物对肿瘤的输送，从而改善治疗反应。这些特定目标的成功完成将产生关于PDAC中STAT3激活机制的重要新知识，并将进一步描述对EGFR、Src和STAT3的整合、功能关系和集体作用的更多了解，这将是获得有效的、多靶点的PDAC治疗所需的。提出的目标具有直接的翻译相关性，因为它们解决了PDAC耐药的一个重要分子机制，并提供了对靶向肿瘤细胞如何通过STAT3抑制剂调节TME以提高对化疗的敏感性的洞察。 与公共卫生相关：与大多数人类癌症相关的基因改变的异质性，使得“一刀切”的方法非常不可能有效。越来越清楚的是，癌症中常见的许多异常信号通路直接导致多种基因的表达和功能的中央调节，这些基因是肿瘤发生和发展的基础。加深对这些关键介质的整合、功能关系和集体作用的理解，对于制定可持续的癌症缓解策略至关重要。

DESCRIPTION (provided by applicant): There is a desperate need for novel treatment strategies for pancreatic ductal adenocarcinoma (PDAC). The long term goal of this proposal is to develop strategies for durable cancer remission by targeting critical mediators of PDAC tumorigenesis and intrinsic drug resistance. Our central hypothesis is that activation of the oncogenic STAT3 pathway represents (a) is involved in intrinsic drug resistance and (b) constitutes a potential therapeutic target for PDAC. The overall objective is to understand the mechanism of constitutive activation of STAT3 in PDAC and determine its downstream biologic effects and clinical relevance. Using gain- and loss-of-function approaches, we will delineate the molecular mechanisms by which STAT3 contributes to PDAC tumorigenesis by defining key target genes and establishing the functional interaction between STAT3, EGFR and Src kinase. We will establish the in vivo effects of STAT3 inhibition using an orthotopic mouse model of PDAC and define the mechanism of interaction of STAT3 signaling within the TME utilizing novel imaging modalities to assess tumor angiogenesis, blood flow, hypoxia and tumor drug delivery in vivo. This will be accomplished by the following specific aims: Aim 1: To investigate the functional role of constitutively activated STAT3 on the pathogenesis and intrinsic drug resistance of PDAC. Hypothesis: The STAT3 transcriptional network is critical in the pathogenesis and chemoresistance of PDAC. Aim 1a will elucidate the mechanism of constitutive activation of STAT3 signaling in PDAC. Aim 1b will determine the biologic effects of STAT3 inhibition and silencing on fundamental target genes. Aim 1c will determine if STAT3 inhibition and silencing overcomes drug resistance in PDAC. Aim 1d will determine the prognostic significance of activated STAT3 in PDAC patients treated with neoadjuvant gemcitabine and erlotinib in a national clinical trial. Aim 2: To determine the contributory roles of EGFR, Src and gemcitabine interaction with STAT3 in overcoming chemoresistance in PDAC. Hypothesis: Combined targeted therapy with STAT3 will overcome redundant signaling pathways and feedback loops associated with STAT3-mediated chemoresistance in PDAC. Aim 3: To determine the mechanism of interaction of STAT3 signaling on the tumor microenvironment in PDAC. The tumor microenvironment (TME) plays a critical role in PDAC. Hypothesis: STAT3 inhibition will promote "vascular normalization" and depletion of stroma, resulting in enhanced drug delivery to the tumor, leading to improved therapeutic response. Successful completion of these specific aims will yield significant new knowledge regarding the mechanism of STAT3 activation in PDAC and will further delineate an increased understanding of the integration, functional relationships and collective roles of EGFR, Src and STAT3 which will be needed to derive effective, multitargeted therapy for PDAC. The aims proposed have direct translational relevance as they address an important molecular mechanism of drug resistance in PDACs and offer insight into how targeting tumor cells with STAT3 inhibitors may modulate the TME to improve sensitivity to chemotherapy. PUBLIC HEALTH RELEVANCE: The heterogeneity of genetic alterations associated with most human cancers, makes it highly unlikely that a "one size fits all" approach will be effective. It is becoming increasingly clear that many of the aberrant signaling pathways commonly seen in cancer lead directly to central regulators of expression and function of a variety of genes that are fundamental to events of tumor development and progression. Delineating an increased understanding of the integration, functional relationships and collective roles of these critical mediators will be essential to develop strategies for durable cancer remission.