Enhanced Chemosensitivity of Pancreatic Cancer

胰腺癌的化疗敏感性增强

• 批准号: 6727208
• 负责人: M GUILLAUME WIENTJES
• 金额: $ 27.21万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6727208
• 关键词: BCL2 gene /protein; antineoplastics; athymic mouse; chemosensitizing agent; clinical research; connective tissue stroma; drug resistance; fibroblast growth factor; growth factor receptors; human tissue; laboratory rat; mitogen activated protein kinase; monoclonal antibody; neoplasm /cancer chemotherapy; nonsmall cell lung cancer; nuclear factor kappa beta; pancreas neoplasms; pharmacokinetics; phosphatidylinositol 3 kinase; suramin; tissue /cell culture

DESCRIPTION (provided by applicant): Patients with advanced pancreatic cancer have a bleak prognosis, with a median survival time of <6 months. Pancreatic cancer is highly resistant to a broad spectrum of chemotherapeutic agents; chemotherapy produces an overall response rate of <10% with little survival advantage. Hence, there is an urgent need for more effective treatments. We recently discovered a new epigenetic mechanism of anticancer drug resistance, that is caused by two fibroblast growth factors expressed in solid tumors, i.e., acidic and basic fibroblast growth factors (aFGF and bFGF). These two proteins, at clinically relevant concentrations, induce an up to 10-fold resistance to drugs with diverse structures and action mechanisms. Inhibitors of these FGFs, including monoclonal antibodies and suramin (at low concentrations with no cytotoxicity), reverse the FGF-induced resistance and enhance the activity of chemotherapy in a number of solid tumor cells in vitro and in vivo. Our results indicate the following: (a) Pancreatic cancer cell lines and pancreatic patient tumors contain high levels of aFGF and bFGF. (b) FGFs induced resistance to drugs that have been used to treat pancreatic cancer. (c) Suramin, a nonspecific FGF antagonist, enhanced the activity of paclitaxel and gemcitabine in human pancreatic cancer cells and xenografts. These findings led to our first hypothesis that aFGF/bFGF is an important resistance mechanism of pancreatic cancer. We also found that FGFs caused different degrees of resistance for different drugs in the same cell line, and that bFGF activated different survival pathways in different cell lines. This led to our second hypothesis that the mechanisms of FGF-induced resistance are context-dependent and vary depending on the cell type and the stress inducer. We further found that suramin enhanced the chemosensitivity of three pancreatic tumors that expressed low, moderate and high FGF levels, leading to our third hypothesis that FGF inhibitors can enhance the chemosensitivity of pancreatic cancer. The goal of this application is to test these hypotheses. Finally, our preclinical results and early clinical results in nonsmall cell lung cancer patients indicate low-dose suramin as an effective chemosensitizer, but that the suramin effect is highly concentration-dependent with chemosensitization at low concentrations and antagonism at high concentrations. We propose to establish the plasma and tissue/tumor pharmacokinetics and pharmacodynamics of suramin in rodents and use these data to establish physiologically based pharmacokinetics models, to identify the optimal treatment schedule and for inter-species scale-up to humans. The proposed research has the potential of identifying a new treatment paradigm for pancreatic cancer.

描述（申请人提供）：晚期胰腺癌患者预后不良，中位生存时间<6个月。胰腺癌对广谱化疗药物具有高度耐药性;化疗产生<10%的总体反应率，几乎没有生存优势。因此，迫切需要更有效的治疗方法。我们最近发现了一种新的抗癌药物抗性的表观遗传机制，其由实体瘤中表达的两种成纤维细胞生长因子引起，即，酸性和碱性成纤维细胞生长因子（aFGF和bFGF）。这两种蛋白质在临床相关浓度下，可诱导对具有不同结构和作用机制的药物产生高达10倍的耐药性。这些FGF的抑制剂，包括单克隆抗体和苏拉明（低浓度，无细胞毒性），逆转FGF诱导的耐药性，并在体外和体内增强许多实体瘤细胞中的化疗活性。我们的结果表明：（a）胰腺癌细胞系和胰腺患者肿瘤含有高水平的aFGF和bFGF。 (b)FGF诱导了对用于治疗胰腺癌的药物的耐药性。(c)苏拉明，一种非特异性FGF拮抗剂，增强了紫杉醇和吉西他滨在人胰腺癌细胞和异种移植物中的活性。这些发现导致我们的第一个假设，aFGF/bFGF是胰腺癌的重要耐药机制。我们还发现，FGF在同一细胞系中对不同药物产生不同程度的耐药性，bFGF在不同细胞系中激活不同的存活途径。这导致了我们的第二个假设， FGF诱导的抗性是环境依赖性的，并且根据细胞类型和应激诱导剂而变化。我们进一步发现苏拉明增强了三种表达低、中、高FGF水平的胰腺肿瘤的化疗敏感性，这导致了我们的第三个假设，即FGF抑制剂可以增强胰腺癌的化疗敏感性。本应用程序的目标是测试这些假设。最后，我们在非小细胞肺癌患者中的临床前结果和早期临床结果表明，低剂量苏拉明是一种有效的化疗增敏剂，但苏拉明的作用是高度浓度依赖性的，在低浓度时具有化疗增敏作用，在高浓度时具有拮抗作用。我们建议建立苏拉明在啮齿类动物中的血浆和组织/肿瘤药代动力学和药效学，并使用这些数据建立基于生理学的药代动力学模型，以确定最佳治疗方案，并用于种间扩大到人类。这项研究有可能为胰腺癌找到一种新的治疗模式。