Enhanced Chemosensitivity of Pancreatic Cancer

胰腺癌的化疗敏感性增强

基本信息

批准号：
7227013
负责人：
M GUILLAUME WIENTJES
金额：
$ 25.8万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7227013
关键词：
Adenocarcinoma Alkylating Agents Antimetabolites Antimitotic Agents Antineoplastic Agents Apoptotic Cancer Patient Cancer cell line Cell Cycle Cell Cycle Progression Cell Line Cells Chemical Structure Chemosensitization Class Clinical Condition Data Dose Drug Efflux Drug Kinetics Drug resistance Ductal Epigenetic Process Excision Fibroblast Growth Factor Fibroblast Growth Factor 2 Fibroblast Growth Factor Receptors G1 Arrest Gemcitabine/Paclitaxel Gene Expression Generations Glutathione S-Transferase Goals Growth Human In Vitro Individual Laboratories Literature Malignant neoplasm of pancreas Monoclonal Antibodies Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Numbers Pancreas Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phase Phase II/III Trial Plasma Play Property Prostate Protein Family Protein Overexpression Proteins Protocols documentation Range Rate Research Research Personnel Resistance Rodent Role Solid Neoplasm Source Stress Structure Suramin Testing Therapeutic Time Tissues Topoisomerase Topoisomerase Inhibitors Toxic effect Treatment Protocols Tumor Tissue Xenograft procedure animal data base cancer cell cell type cellular engineering chemosensitizing agent chemotherapeutic agent chemotherapy clinically relevant cytotoxicity desire gemcitabine in vivo inhibitor/antagonist lymph nodes neoplastic cell outcome forecast pancreatic neoplasm paracrine pharmacokinetic model pre-clinical programs resistance mechanism response scale up subcutaneous tumor tumor xenograft uptake

项目摘要

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黯淡，中位生存时间<6个月。胰腺癌对多种化疗药物具有高度耐药性；化疗的总体缓解率<10%，且生存优势甚微。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耐药性表观遗传机制，该机制是由实体瘤中表达的两种成纤维细胞生长因子，即酸性和碱性成纤维细胞生长因子（aFGF和bFGF）引起的。这两种蛋白质在临床相关浓度下，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），可逆转 FGF 诱导的耐药性，并增强体外和体内许多实体瘤细胞的化疗活性。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 诱导对用于治疗胰腺癌的药物产生耐药性。 (c) 苏拉明是一种非特异性 FGF 拮抗剂，可增强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 是胰腺癌的重要抵抗机制。我们还发现FGF在同一细胞系中对不同药物引起不同程度的耐药性，并且bFGF在不同细胞系中激活不同的生存途径。这引出了我们的第二个假设，即该机制 FGF 诱导的抵抗力是环境依赖性的，并且根据细胞类型和应激诱导物而变化。我们进一步发现苏拉明增强了表达低、中和高FGF水平的三种胰腺肿瘤的化疗敏感性，从而得出我们的第三个假设：FGF抑制剂可以增强胰腺癌的化疗敏感性。此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，但苏拉明的作用高度依赖于浓度，低浓度下有化疗增敏作用，高浓度下有拮抗作用。我们建议在啮齿类动物中建立苏拉明的血浆和组织/肿瘤药代动力学和药效学，并利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在人类之间进行物种间推广。拟议的研究有可能确定胰腺癌的新治疗模式。