The role of the stromal cell surface protease FAP in pancreatic cancer

描述(申请人提供)：胰腺导管腺癌(PDAC)目前还没有有效的治疗方法，只有不到4%的患者在确诊后5年内存活。随着PDAC发病率的上升，我们迫切需要扩大对促进PDAC发生、发展、转移和耐药机制的认识，为开发新的治疗方法铺平道路。有证据表明，除了肿瘤细胞固有的致癌和抑癌途径的缺陷外，来自肿瘤微环境(TME)的外在信号在PDAC中也起着关键作用。炎症细胞、基质细胞、细胞外基质(ECM)和蛋白水解酶是TME促进肿瘤形成和产生耐药性的组成部分。最近的研究表明，干扰外部信号(包括声波刺激物、赖氨酰氧化酶、成纤维细胞激活蛋白(FAP)或CD40)可以抑制包括PDAC在内的各种肿瘤类型的发展和/或进展。尽管这些研究针对的是不同的途径，但它们揭示了肿瘤微环境中细胞外基质的含量和/或组织的变化可能是它们影响肿瘤发生的共同机制。FAP是一种细胞表面丝氨酸蛋白酶，选择性表达于肿瘤相关间质细胞(包括PDAC)，在肺癌和结肠癌模型的TME中ECM的重塑中起关键作用。在拟议的研究中，我们将使用遗传学方法将这些研究扩展到两种PDAC的基因工程小鼠模型，以检验FAP促进PDAC发展和/或进展的假设，并确定涉及的机制。为了确定靶向FAP的翻译潜力，我们还将确定在这些PDAC基因工程小鼠模型中，药物抑制FAP是否作为单一疗法抑制PDAC进展或增强化疗的有效性。

DESCRIPTION (provided by applicant): There are no effective treatments for pancreatic ductal adenocarcinma (PDAC), accounting for the abysmal statistic of fewer than 4% of patients surviving 5 years beyond diagnosis. With the incidence of PDAC on the rise it is increasingly urgent that we expand our knowledge of the mechanisms that promote the development, progression, metastasis and drug resistance of PDAC, to pave the way for the development of new therapeutic modalities. There is compelling evidence that in addition to the defects in oncogenic and tumor suppressor pathways intrinsic to the malignant tumor cells, extrinsic signals from the tumor microenvironment (TME) also play critical roles in PDAC. Inflammatory cells, stromal cells, extracellular matrix (ECM), and proteases are amongst the components of the TME that promote tumorigenesis and contribute to drug resistance. Recent studies indicate that disrupting extrinsic signals (including sonic hedgehog, lysyl-oxidase, fibroblast activation protein (FAP) or CD40) can inhibit the development and/or progression of tumors in various tumor types including PDAC. Although these studies targeted distinct pathways, they revealed that alterations in the content and/or organization of the extracellular matrix in the tumor microenvironment may be a common mechanism underlying their impact on tumorigenesis. FAP is a cell surface serine protease selectively expressed on carcinoma associated stromal cells (including PDAC) that we have shown plays a critical role in remodeling the ECM in the TME of lung and colon cancer models. In the proposed studies, using a genetic approach we will extend these studies to two genetically engineered mouse models of PDAC to test the hypothesis that FAP promotes the development and/or progression of PDAC and define the mechanisms involved. To determine the translational potential of targeting FAP, we will also determine whether pharmacologic inhibition of FAP inhibits PDAC progression as a monotherapy or enhances efficacy of chemotherapy in these genetically engineered mouse models of PDAC.