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（pancreatic ductal adencarcinoma， PDA）没有有效的治疗方法，在确诊后存活5年的患者中，只有不到4%的患者统计数据非常糟糕。随着PDA发病率的上升，我们越来越迫切地需要扩大对促进PDA发生、进展、转移和耐药机制的认识，为开发新的治疗方式铺平道路。有令人信服的证据表明，除了恶性肿瘤细胞固有的致癌和抑瘤途径的缺陷外，来自肿瘤微环境（TME）的外在信号也在PDA中发挥关键作用。炎症细胞、基质细胞、细胞外基质（ECM）和蛋白酶是TME中促进肿瘤发生和促进耐药的成分。最近的研究表明，干扰外部信号（包括超音hedgehog基因、赖氨酸氧化酶、成纤维细胞激活蛋白（FAP）或CD40）可以抑制包括PDA在内的各种肿瘤类型的肿瘤发生和/或进展。尽管这些研究针对不同的途径，但它们揭示了肿瘤微环境中细胞外基质的含量和/或组织的改变可能是其影响肿瘤发生的共同机制。FAP是一种选择性表达于癌相关基质细胞（包括PDA）的细胞表面丝氨酸蛋白酶，我们已经证明它在肺癌和结肠癌TME模型的ECM重塑中起关键作用。在拟议的研究中，我们将使用遗传方法将这些研究扩展到两个PDA基因工程小鼠模型，以验证FAP促进PDA发展和/或进展的假设，并确定相关机制。为了确定靶向FAP的转化潜力，我们还将确定在这些基因工程小鼠PDA模型中，FAP的药物抑制是作为单一疗法抑制PDA的进展，还是增强化疗的疗效。

DESCRIPTION (provided by applicant): There are no effective treatments for pancreatic ductal adenocarcinma (PDA), accounting for the abysmal statistic of fewer than 4% of patients surviving 5 years beyond diagnosis. With the incidence of PDA 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 PDA, 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 PDA. 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 PDA. 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 PDA) 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 PDA to test the hypothesis that FAP promotes the development and/or progression of PDA and define the mechanisms involved. To determine the translational potential of targeting FAP, we will also determine whether pharmacologic inhibition of FAP inhibits PDA progression as a monotherapy or enhances efficacy of chemotherapy in these genetically engineered mouse models of PDA.