The Role of CXCR2 in Pancreatic Cancer

描述（由申请人提供）：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32，000例新病例和欧洲每年60，000例新病例中的大多数将在诊断后一年内死亡。 目前迫切需要开发新的更好的胰腺癌治疗策略。 与其他实体瘤一样，我们和其他人发现抑制VEGF可以减缓胰腺癌的体内进展。 然而，这些研究也表明，这种方法不能完全阻断肿瘤相关的血管生成，这表明还涉及其他因素。 在临床上，人源化VEGF抗体的使用已经证明了一些实用性，但没有提供太多的存活优势。 我们实验室的初步证据表明，CXC趋化因子是胰腺癌生长紊乱和血管生成的重要介质。 几种CXC趋化因子是有效的血管生成因子，并且代表通过单一受体CXC受体2（CXCR 2）发挥促进血管生成的独特细胞因子家族。 阻断CXCR 2可能是减缓血管生成和预防肿瘤发生的有力策略。 我们假设胰腺癌的进展是由特定的血管生成CXC趋化因子的表达和相应受体CXCR 2的激活促进的;并且抑制CXCR 2将延迟与抑制血管生成相关的胰腺癌的生长和转移。 具体目的I）确定CXCR 2配体与VEGF相比是否与体内肿瘤生长相关，以及CXCR 2抑制是否消除原位鼠模型中胰腺癌的血管生成、局部生长和转移;具体目标II）确定胰腺癌患者中CXCR 2和CXCR 2配体的循环和肿瘤水平是否与胰腺癌的程度相关。血管生成、疾病阶段和存活率。 为了完成这些目标，我们将在胰腺癌原位模型中进行三个实验，以通过（1）抗体和（2）CXCR 2-/-鼠模型中的生长抑制CXCR 2。 将治疗组与针对VEGFR 2的治疗进行比较，并进行组合，以评估这两个系统的贡献。 最后，我们的大量胰腺癌患者临床数据将用于评估CXCR 2配体和CXCR 2，因为它们与分期和预后相关。 胰腺癌是一种毁灭性的疾病，今年在美国将导致超过32，000人死亡（1）。 对于患有这种疾病的患者来说，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这种癌症的扩散。 该项目研究了负责这种血管生长的两个系统，CXC趋化因子和VEGF对胰腺癌生长的影响，并建立了这些蛋白质与胰腺癌患者的关系。

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.