TGF-beta Signaling in Pancreatic Cancer

说明(申请人提供)：转化生长因子-？(转化生长因子？)信号通路在胰腺导管腺癌(PDAC)的发病机制中具有双重作用：抑制肿瘤的早期发展，促进晚期肿瘤的生长。Smad4，一个中心的转化生长因子？在大约50%的人PDAC中，Smad4基因突变，Smad4突变促进了小鼠的PDAC，这与肿瘤抑制功能一致。另一方面，支持转化生长因子的证据呢？Path在促进已建立的癌症生长方面的作用包括从人类研究和我们的小鼠模型中观察到的一些结果。具体地说，1)转化生长因子？通路激活与晚期人类PDAC有关，以及2)阻断转化生长因子？途径抑制人和小鼠PDAC细胞亚群的致瘤性。根据我们的初步数据，我们假设，转化生长因子-β/Smad4信号a)在早期阶段抑制肿瘤的启动和进展，但b)促进晚期PDAC的子集的恶性生长。因此，转化生长因子的抑制剂？信号转导可能在治疗转移性PDAC的亚组中有效。这项建议描述了一种系统的方法来理解转化生长因子？通路功能贯穿于胰腺导管肿瘤发生的各个阶段。这些研究将使用能够实现时间调节的转化生长因子？激活和失活的改进的小鼠模型。体内信号和体内信号。我们还将使用药理学方法来解除对该途径的管制。最后，我们将在具有已知分子特征的PDAC细胞系中进行高通量分析，以确定能够预测对转化生长因子？路径。其具体目的是(1)明确Smad4调控PDAC前体病变(Panins)进展的机制和随后发生的肿瘤的表型；(2)探讨转化生长因子？信号转导作为晚期PDAC治疗的靶点；(3)确定转化生长因子？促进肿瘤发生和定义转化生长因子分子标志物的途径成分？PDAC中的响应性。 与公共健康相关：PDAC是美国癌症死亡的第四大原因，对所有现有的治疗方法都具有耐药性。我们的研究将定义转化生长因子所扮演的生物学角色？在PDAC进展过程中传递信号，从而提供对该途径作为药物靶点的潜力的洞察。 与公共健康相关：基于在包括PDAC在内的许多晚期癌症中观察到的活性增加，TGFbeta途径被认为是一个很好的药物靶点。虽然一些制药公司已经开发了特定的抗TGFbeta药物，但由于该途径在限制癌症发生方面的相反作用，它们的使用变得复杂。我们提出的实验将直接研究转化生长因子-β信号在PDAC进展的不同阶段中的作用。详细了解这一生化途径的变化如何影响肿瘤发生，将有助于根据患者的疾病阶段和突变情况决定如何使用这些药物。

DESCRIPTION (provided by applicant): The transforming growth factor-? (TGF?) signaling pathway appears to play dual roles in pancreatic ductal adenocarcinoma (PDAC) pathogenesis; restraining the early stages of tumor development while promoting the growth of advanced cancers. Smad4, a central TGF? pathway effector, is mutated in ~50% of human PDAC, and Smad4 mutations promote PDAC in mice, consistent with a tumor suppressor function. On the other hand, evidence supporting the TGF? pathway's role in promoting growth of established cancers includes a number of observations from human studies and from our mouse models. Specifically, 1) TGF? pathway activation is associated with advanced human PDAC, and 2) blockade of the TGF? pathway inhibits tumorigenicity of a subset of human and mouse PDAC cells lines. Based on our preliminary data, we hypothesize that TGF-?/Smad4 signaling a) restrains tumor initiation and progression at early stages but b) promotes the malignant growth of a subset of advanced PDAC. Hence inhibitors of TGF? signaling are likely to be effective in the treatment of a subset of metastatic PDAC. This proposal describes a systematic approach to understanding TGF? pathway function throughout each stage of pancreatic ductal tumorigenesis. These studies will employ refine mouse models that enable temporally regulated activation and inactivation of TGF? signaling in vivo and in vivo. We will also use pharmacological approaches to deregulate the pathway. Finally, we will conduct high-throughput assays in PDAC cell lines with known molecular profiles to define markers able to predict responsiveness to TGF? pathway. The Specific Aims are (1) Define the mechanisms by which Smad4 regulates progression of PDAC precursor lesions (PanINs) and the phenotypes of ensuing tumors; (2) Explore TGF? signaling as a target for treatment in advanced PDAC; (3) Determine TGF? pathway components that contribute to tumorigenesis and define molecular markers of TGF? responsiveness in PDAC. Relevance to public health: PDAC is the fourth leading cause of cancer mortality in the United States and is resistant to all existing therapies. Our studies will define the biological roles played by TGF? signaling throughout the course of PDAC progression and thereby provide insight into the potential of this pathway as a drug target. PUBLIC HEALTH RELEVANCE: The TGFbeta pathway is thought to be a good drug target based on the increased activity observed in many advanced cancers including PDAC. While a number of pharmaceutical companies have developed specific anti-TGFbeta drug, their use is complicated by the opposing role of the pathway in limiting cancer initiation. Our proposed experiments will directly investigate the role of TGF-beta signaling at different stages of PDAC progression. The detailed understanding of how alterations in this biochemical pathway affect tumorigenesis will inform help in deciding how to use these drugs in patients in relation to the stage and mutational profile of their disease.