The Role of CXCR2 in Pancreatic Cancer

描述(申请人提供)：胰腺癌是美国癌症相关死亡的第四大原因。据估计，美国每年新增病例3.2万例，欧洲每年新增病例6万例，其中大多数将在确诊后一年内死亡。迫切需要开发新的更好的治疗胰腺癌的策略。与其他实体肿瘤一样，我们和其他人发现抑制血管内皮生长因子可以减缓体内胰腺癌的进展。然而，这些研究也表明，这种方法并不能完全阻断肿瘤相关的血管生成，这表明还有其他因素参与其中。临床上，人源化血管内皮生长因子抗体的使用显示了一定的实用性，但并没有提供太多的生存优势。我们实验室的初步证据表明，CXC趋化因子是胰腺癌无序生长和血管生成的重要介质。一些CXC趋化因子是强大的血管生成因子，代表着一个独特的细胞因子家族，通过单个受体CXC受体2(CXCR2)发挥促进血管生成的作用。阻断CXCR2可能是减缓血管生成和防止肿瘤发生的有效策略。我们假设，胰腺癌的进展是通过表达特异性的血管生成CXC趋化因子并激活相应的受体CXCR2来促进的；抑制CXCR2将通过抑制血管生成来延缓胰腺癌的生长和转移。我们将致力于以下具体目标：1)确定CXCR2配体与血管内皮生长因子相比是否与体内肿瘤生长相关，以及抑制CXCR2是否能抑制原位小鼠胰腺癌的血管生成、局部生长和转移；2)明确胰腺癌患者循环和肿瘤中CXCR2和CXCR2配体的水平是否与血管生成程度、疾病分期和生存期相关。为了实现这些目标，我们将在胰腺癌原位模型中进行三个实验，以(1)抗体和(2)CXCR2-/-小鼠模型中的生长抑制CXCR2。治疗组将与针对VEGFR2的治疗进行比较，并结合使用，以评估这两个系统的贡献。最后，我们的大量胰腺癌患者的临床数据量将被用于评估CXCR2配体和CXCR2，因为它们与分期和预后相关。胰腺癌是一种毁灭性的疾病，今年将导致美国超过32,000人死亡[1]。对于这种疾病的患者，一种潜在的治疗方法是通过阻止肿瘤内部和周围血管的生长来阻止癌症的扩散。这个项目调查了两个负责血管生长的系统，CXC趋化因子和血管内皮生长因子，对胰腺癌生长的影响，并建立了这些蛋白与胰腺癌患者胰腺癌的关系。

DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Most of the estimated 32,000 annual new cases in the U.S. and 60,000 annual new cases in Europe will die within a year of diagnosis. There is an urgent need to develop new and better strategies for the treatment of pancreatic cancer. As with other solid tumors, we and others have found that inhibition of VEGF can slow the progression of pancreatic cancer in vivo. However, these studies have also shown that this approach does not completely block tumor associated angiogenesis suggesting that other factors are involved. Clinically, the use of humanized VEGF antibody has demonstrated some utility, but has not provided much survival advantage. Preliminary evidence in our laboratory suggests that CXC chemokines are important mediators of disordered growth and angiogenesis in pancreatic cancer. Several CXC chemokines are potent angiogenic factors and represent a unique family of cytokines that exert promotion of angiogenesis through a single receptor CXC receptor 2 (CXCR2). Blockade of CXCR2 is potentially a powerful strategy to slow angiogenesis and prevent tumorigenesis. We hypothesize that the progression of pancreatic cancer is promoted by the expression of specific angiogenic CXC chemokines and activation of the corresponding receptor, CXCR2; and that inhibition of CXCR2 will delay the growth and metastasis of pancreatic cancer related to inhibition of angiogenesis. We will pursue the following specific aims: Specific Aim I) Determine whether CXCR2 ligands as compared to VEGF correlate with tumor growth in vivo, and whether CXCR2 inhibition abrogates angiogenesis, local growth and metastasis of pancreatic cancer in an orthotopic murine model; Specific Aim II) Determine whether circulating and tumor levels of CXCR2 and CXCR2 ligands in patients with pancreatic cancer are correlated with degree of angiogenesis, stage of disease, and survival. To complete these aims we will perform three experiments in a pancreatic cancer orthotopic model to inhibit CXCR2 by (1) antibody, and (2) growth in a CXCR2-/- murine model. Treatment groups will be compared to treatment against VEGFR2, and in combination, in order to assess the contribution of these two systems. Finally, our large clinical volume of patients with pancreatic cancer will be utilized to evaluate CXCR2 ligands and CXCR2 as these correlate to stage and prognosis. Pancreatic cancer is a devastating disease and will be responsible for more than 32,000 deaths in the United States this year (1). A potential therapy for patients with this disease would be to stop the spread of this cancer by stopping the growth of blood vessels into and around the tumor. This project investigates the impact of two systems responsible for this blood vessel growth, CXC chemokines and VEGF, on the growth of pancreatic cancer and also establishes the relationship of these proteins to pancreatic cancer in patients with this disease.