Chemoresistance in Renal Cell Cancer

描述（由申请人提供）：转移性肾细胞癌（RCC）患者预后惨淡，平均生存时间不到18个月。因此，迫切需要更有效的治疗方法。RCC对化疗的总体反应率<10%，对不同类型的药物具有不同的作用或耐药机制。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FGF的抑制剂，包括单克隆抗体和苏拉明（低浓度，无细胞毒性），完全逆转FGF诱导的耐药并增强化疗活性。在动物实验中，低剂量和无毒剂量的苏拉明显著提高了化疗的疗效，导致免疫缺陷小鼠体内肿瘤的根除。除了这些早期对前列腺肿瘤细胞进行的研究外，我们还获得了以下数据。(a)从患者身上获得的肾细胞癌细胞系和肾细胞癌组织含有高水平的aFGF/bFGF。(b)对用于治疗RCC的药物观察到FGF诱导的耐药，并被FGF抑制剂逆转。(c) aFGF/bFGF诱导其他人类实体瘤细胞（即肺、卵巢、结肠、咽部）耐药。(d) FGF抑制剂（苏拉明和/或聚硫酸戊聚糖）增强了5-氟尿嘧啶和吉西他滨在两种肾细胞癌细胞系和肾细胞癌患者肿瘤组织培养物中的抗肿瘤活性。(e)与其他已知的预后指标（如p53突变、Bcl2和mdr1 p糖蛋白过表达和肿瘤病理）相比，bFGF表达能更好地预测多种类型人类肿瘤的紫杉醇耐药。(e) cDNA微阵列分析结果显示，bFGF增强了几种已知化学耐药机制相关基因（GST、Bcl-2家族蛋白、拓扑异构酶和药物外排蛋白）的表达，而苏拉明则降低了这些基因和FGF受体的表达。为了评估我们的发现的临床应用，我们启动了一项I/Il期试验，使用低剂量苏拉明来增强紫杉醇和卡铂在晚期非小细胞肺癌患者中的疗效。完成的I期试验的初步结果支持这样的假设，即与仅使用紫杉醇/卡铂治疗的患者组的历史数据相比，低剂量和无毒剂量的苏拉明可提高缓解率，延长无进展生存期和延长中位生存时间。基于这些发现，我们假设(a) aFGF/bFGF是RCC化疗耐药的重要机制，(b) aFGF/bFGF抑制剂可以增强RCC化疗的疗效。本申请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。提出的研究有可能确定一种新的治疗RCC的范例。

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.