Chemoresistance in Renal Cell Cancer

肾细胞癌的化疗耐药性

• 批准号: 7087930
• 负责人: Jessie L.-S. Au
• 金额: $ 26.19万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-08 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087930
• 关键词: antineoplastics; athymic mouse; carboplatin; clinical research; clinical trial phase I; clinical trial phase II; drug resistance; fibroblast growth factor; gene expression; glutathione; glutathione transferase; growth factor receptors; human subject; human therapy evaluation; immunocytochemistry; neoplasm /cancer chemotherapy; paclitaxel; patient oriented research; pentosan; receptor expression; renal cell carcinoma; sulfates; suramin

DESCRIPTION (provided by applicant): Patients with metastatic renal cell cancer (RCC) have a bleak prognosis with an average survival time of less than 18 months. Hence, there is an urgent need of more effective treatments. RCC show an overall response rate of <10% to chemotherapy and is resistance to different classes of drugs that do not share the same action or resistance mechanisms. 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 FGF, including the monoclonal antibodies and suramin (at low concentrations with no cytotoxicity), completely reverse the FGF-induced resistance and enhance the activity of chemotherapy. In animals, low and nontoxic doses of suramin significantly enhanced the efficacy of chemotherapy, resulting in eradication of well- established tumors in immunodeficient mice. In addition to these earlier studies conducted with prostate tumor cells, we have obtained data showing the following. (a) RCC cell lines and RCC tissues obtained from patients contained high levels of aFGF/bFGF. (b) The FGF-induced resistance was observed for drugs that have been used to treat RCC, and was reversed by FGF inhibitors. (c) aFGF/bFGF induced chemoresistance in other human solid tumor cells (i.e., lung ovarian, colon, pharynx). (d) FGF inhibitors (suramin and/or pentosan polysulfate) enhanced the antitumor activity of 5-fluorouracil and gemcitabine in two RCC cell lines and histocultures of RCC patient tumors. (e) bFGF expression was a better predictor of paclitaxel resistance in multiple types of human tumors, compared to other known prognostic indicators (i.e., mutated p53, overexpression of Bcl2 and the mdr1 p-glycoprotein, and tumor pathology). (e) Results of cDNA microarray analysis show that bFGF enhanced the expression of genes involved in several known chemoresistance mechanisms (GST, Bcl-2 family proteins, topoisomerase, and drug efflux proteins), whereas suramin reduced the expression of these genes and FGF receptors. To evaluate the clinical application of our findings, we initiated a phase I/Il trial using low dose suramin to enhance the efficacy of paclitaxel and carboplatin, in advanced non-small cell lung cancer patients. The preliminary results of the completed phase I trial support the hypothesis that low and nontoxic doses of suramin enhanced the response rate, prolonged the progression-free survival and prolonged the median survival time, as compared to the historical data in this patient group treated with only paclitaxel/carboplatin. Based on these findings, we hypothesize that (a) aFGF/bFGF is an important resistance mechanism of RCC to chemotherapy, and (b) aFGF/bFGF inhibitors can enhance the efficacy of chemotherapy in RCC. The overall goal of this application is to test these hypotheses in preclinical (Aims 1 to 3) and clinical (Aims 4 and 5) studies. The proposed research has the potential of identifying a new treatment paradigm for RCC.

描述（由申请人提供）：转移性肾细胞癌（RCC）的患者的预后黯淡，平均生存时间少于18个月。因此，迫切需要更有效的治疗方法。 RCC对化学疗法的总体反应率<10％，并且对不同类别的药物的耐药性不具有相同的作用或抗药性机制。我们最近发现了一种新的抗癌耐药性表观遗传机制，该机制是由在实体瘤中表达的两个成纤维细胞生长因子引起的，即酸性和碱性成纤维细胞生长因子（AFGF和BFGF）。这两种在临床相关浓度下的蛋白质可引起对具有不同结构和作用机制的药物的10倍耐药性。这些FGF的抑制剂，包括单克隆抗体和苏拉蛋白（低浓度，无细胞毒性），完全逆转了FGF诱导的耐药性并增强了化学疗法的活性。在动物中，低剂量和无毒的苏拉素可显着提高化学疗法的功效，从而消除免疫缺陷小鼠中良好的肿瘤。除了前列腺肿瘤细胞进行的这些早期研究外，我们还获得了以下数据。 （a）从患者获得的RCC细胞系和RCC组织中含有高水平的AFGF/BFGF。 （b）观察到用于治疗RCC的药物的FGF诱导的耐药性，并被FGF抑制剂逆转。 （C）AFGF/BFGF在其他人类实体瘤细胞中诱导的化学耐药性（即肺卵巢，结肠，咽）。 （d）FGF抑制剂（Suramin和/或Pentosan多硫酸盐）增强了RCC患者肿瘤的两个RCC细胞系和组织培养物中5-氟尿嘧啶和吉西他滨的抗肿瘤活性。 （e）与其他已知的预后指标（即突变的p53，BCL2的过表达和MDR1 P-糖蛋白和肿瘤病理学）相比，BFGF表达是多种类型人类肿瘤中紫杉醇抗性的更好预测指标。 （e）cDNA微阵列分析的结果表明，BFGF增强了参与几种已知的化学抗性机制（GST，BCL-2家族蛋白，拓扑异构酶和药物外排蛋白）的基因的表达，而Suramin降低了这些基因和FGF受体的表达。为了评估我们发现的临床应用，我们使用低剂量苏拉蛋白开始了I/IL期试验，以增强晚期非小细胞肺癌患者的紫杉醇和卡铂的功效。完整的I期试验的初步结果支持了以下假设：与仅用paclitaxel/carboplatin治疗的患者组相比，与该患者组中的历史数据相比，与该患者组中的历史数据相比，苏拉米蛋白提高了反应率，延长了无进展的生存时间并延长了中位生存时间。基于这些发现，我们假设（a）AFGF/BFGF是RCC对化学疗法的重要抗药性机制，并且（b）AFGF/BFGF抑制剂可以增强RCC化疗的功效。该应用的总体目标是在临床前（目标1至3）和临床（目标4和5）研究中检验这些假设。拟议的研究有可能识别RCC的新治疗范式。