Enhanced Chemosensitivity of Pancreatic Cancer

描述（申请人提供）：晚期胰腺癌患者预后惨淡，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；化疗产生的总有效率<10%，生存优势很小。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肿瘤耐药的表观遗传机制，这种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FGFs的抑制剂，包括单克隆抗体和苏拉明（低浓度无细胞毒性），在体外和体内逆转了fgf诱导的耐药性，并增强了许多实体瘤细胞的化疗活性。结果表明：(a)胰腺癌细胞系和胰腺患者肿瘤中含有高水平的aFGF和bFGF。(b) FGFs诱导对用于治疗胰腺癌的药物产生耐药性。(c)苏拉明，一种非特异性FGF拮抗剂，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。这些发现导致了我们的第一个假设，即aFGF/bFGF是胰腺癌的重要耐药机制。我们还发现，fggf在同一细胞系中对不同药物产生不同程度的耐药，并且bFGF在不同细胞系中激活了不同的生存途径。这就引出了我们的第二个假设

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.