Stat3 Signaling in Pancreas Cancer

胰腺癌中的 Stat3 信号转导

• 批准号: 8441523
• 负责人: NIPUN B. MERCHANT
• 金额: $ 30.43万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441523
• 关键词: Address; Adenocarcinoma Cell; Biological Markers; Blood Vessels; Blood flow; Cancer Remission; Clinical Trials; Communication; Data; Desmoplastic; Development; Drug Delivery Systems; Drug resistance; Epidermal Growth Factor Receptor; Erlotinib; Event; Failure; Feedback; Gene Targeting; Genes; Genetically Engineered Mouse; Goals; Heterogeneity; Human; Hypoxia; Indium; Intercellular Fluid; Interruption; Knowledge; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Mutation; Neoadjuvant Therapy; Normal Cell; Nutrient; Oncogenic; Oxygen; Pancreatic Ductal Adenocarcinoma; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Protein Tyrosine Kinase; Resistance; Role; Signal Pathway; Signal Transduction; Stat3 protein; Therapeutic; Tumor Angiogenesis; angiogenesis; cancer therapy; chemotherapy; clinically relevant; gemcitabine; imaging modality; improved; in vivo; inhibitor/antagonist; insight; loss of function; mouse model; neoplastic cell; novel; novel strategies; pressure; prognostic; response; src-Family Kinases; therapeutic target; transcription factor; treatment strategy; tumor; tumor microenvironment; tumorigenesis

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.

描述（由申请人提供）：迫切需要胰腺导管腺癌（PDAC）的新型治疗策略。该提案的长期目标是通过靶向PDAC肿瘤发生和内在耐药性的关键介质来开发持久癌症缓解的策略。我们的中心假设是致癌性STAT3通路的激活代表（a）参与内在耐药性和（B）构成PDAC的潜在治疗靶点。总体目标是了解PDAC中STAT3组成性激活的机制，并确定其下游生物学效应和临床相关性。使用获得和丧失功能的方法，我们将描绘STAT3有助于PDAC肿瘤发生的分子机制，通过定义关键的靶基因，并建立STAT3，EGFR和Src激酶之间的功能相互作用。我们将使用PDAC的原位小鼠模型建立STAT3抑制的体内效应，并利用新的成像方式来评估肿瘤血管生成、血流、缺氧和体内肿瘤药物递送，从而定义TME内STAT3信号传导的相互作用机制。这将通过以下具体目标来实现：目标1：探讨组成性激活的STAT 3在PDAC发病机制和内在耐药性中的功能作用。假设：STAT3转录网络在PDAC的发病机制和耐药性中至关重要。目的1a阐明STAT3信号在PDAC中的组成性激活机制。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STAT3抑制和沉默是否克服PDAC中的耐药性。目的1d将确定在国家临床试验中使用新辅助吉西他滨和厄洛替尼治疗的PDAC患者中活化的STAT3的预后意义。目的2：确定EGFR、Src和吉西他滨与STAT3相互作用在克服PDAC化疗耐药性中的贡献作用。假设：与STAT3的组合靶向治疗将克服与PDAC中STAT3介导的化疗耐药性相关的冗余信号通路和反馈环。目的3：探讨STAT3信号通路在PDAC肿瘤微环境中的相互作用机制。肿瘤微环境（TME）在PDAC中起着关键作用。假设：STAT3抑制将促进“血管正常化”和基质的消耗，导致增强的药物递送至肿瘤，从而导致改善的治疗反应。成功完成这些特定目标将产生有关PDAC中STAT 3激活机制的重要新知识，并将进一步加深对EGFR、Src和STAT 3的整合、功能关系和集体作用的理解，这是获得有效的多靶点所需的PDAC治疗。提出的目标具有直接的翻译相关性，因为它们解决了PDAC中耐药性的重要分子机制，并提供了对STAT3抑制剂靶向肿瘤细胞如何调节TME以提高对化疗敏感性的见解。