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

描述（由申请人提供）：胰腺导管腺癌（PDAC）尚无有效治疗方法，诊断后存活5年的患者不到4%。随着PDAC发病率的不断上升，对PDAC发生、发展、转移和耐药机制的认识日益迫切，为开发新的治疗方法铺平道路。有令人信服的证据表明，除了恶性肿瘤细胞内在的致癌和抑癌途径的缺陷外，来自肿瘤微环境（TME）的外源性信号在PDAC中也起着关键作用。炎性细胞、基质细胞、细胞外基质（ECM）和蛋白酶是TME的组分之一，其促进肿瘤发生并有助于耐药性。最近的研究表明，破坏外源性信号（包括音刺猬，赖氨酰氧化酶，成纤维细胞活化蛋白（FAP）或CD40）可以抑制各种肿瘤类型（包括PDAC）中肿瘤的发展和/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对肿瘤发生影响的共同机制。FAP是一种选择性表达于癌相关基质细胞（包括PDAC）上的细胞表面丝氨酸蛋白酶，我们已经证明其在肺癌和结肠癌模型的TME中重塑ECM中起关键作用。在拟议的研究中，使用遗传学方法，我们将这些研究扩展到两个基因工程小鼠模型的PDAC，以测试的假设，FAP促进PDAC的发展和/或进展，并定义所涉及的机制。为了确定靶向FAP的翻译潜力，我们还将确定FAP的药理学抑制是否作为单一疗法抑制PDAC进展或在这些基因工程PDAC小鼠模型中增强化疗的功效。

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.