Enhanced Chemosensitivity of Pancreatic Cancer

描述(申请人提供)：晚期胰腺癌患者预后黯淡，中位生存期为6个月。胰腺癌对广谱化疗药物高度耐药；化疗的总有效率为10%，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耐药的表观遗传学机制，即在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)。这两种蛋白在临床相关浓度下，对具有不同结构和作用机制的药物诱导高达10倍的耐药性。这些FGFs的抑制剂，包括单抗和苏拉明(在低浓度下没有细胞毒性)，在体内外逆转了成纤维细胞生长因子诱导的耐药性，并增强了化疗的活性。我们的结果表明：(A)胰腺癌细胞株和胰腺癌患者肿瘤细胞中含有高水平的aFGF和bFGF。(B)FGFs导致对已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成纤维细胞生长因子拮抗剂，可增强人胰腺癌细胞和异种移植瘤中紫杉醇和吉西他滨的活性。这些发现导致了我们的第一个假设，即aFGF/bFGF是胰腺癌重要的耐药机制。我们还发现，成纤维细胞生长因子在同一细胞系中对不同的药物产生不同程度的耐药性，而碱性成纤维细胞生长因子在不同的细胞系中激活了不同的生存途径。这导致了我们的第二个假设，即 成纤维细胞生长因子诱导的抗性是上下文相关的，并随细胞类型和压力诱导剂的不同而变化。我们进一步发现苏拉明增强了三种胰腺肿瘤的化疗敏感性，这些肿瘤表达低、中、高水平的成纤维细胞生长因子，这导致了我们的第三个假设，即成纤维细胞生长因子抑制剂可以增强胰腺癌的化疗敏感性。这个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和早期临床结果表明，小剂量苏拉明是一种有效的化疗增敏剂，但苏拉明的作用具有高度的浓度依赖性，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体内的血浆和组织/肿瘤药代动力学和药效学，并利用这些数据建立基于生理的药代动力学模型，确定最佳治疗方案，并将其扩大到人类的物种间。这项拟议的研究有可能确定胰腺癌的新治疗范例。

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.