Treatment of Chemotherapy-Resistant Human Ovarian Cancer by Administration of CPE

描述（申请人提供）：卵巢癌仍然是妇科肿瘤中死亡率最高的癌症。尽管许多卵巢癌患者对手术和化疗的标准组合完全有效，但近90%的患者后来发展为复发性化疗耐药癌症，并不可避免地死于疾病。因此，开发针对复发性/化疗耐药卵巢癌的创新、有效疗法仍然是改善公众健康的高度优先事项。利用高通量技术分析卵巢癌的遗传指纹，我们最近发现了编码蛋白质claudin-3和claudin-4的基因的极高表达。由于claudin-3和-4是产气荚膜梭菌肠毒素（CPE）的上皮受体，足以介导CPE的结合，从而引发随后的毒素介导的细胞溶解，我们假设基于CPE的高水平claudin-3和-4靶向卵巢癌细胞可能是一种新的、高效的化疗耐药卵巢癌治疗方法。与这一观点一致的是，我们将CPE引入过表达cludin -3和-4的原发、转移和化疗耐药卵巢癌培养细胞，我们发现这些肿瘤细胞与健康的人类组织不同，对CPE介导的细胞溶解高度敏感。更重要的是，我们发现腹腔内CPE治疗含有高度相关的化疗耐药人类卵巢癌临床模型的SCID小鼠异种移植物，可以100%抑制已建立疾病1周的小鼠的肿瘤生长。因此，使用CPE靶向高水平的claudin-3和-4可能是一种创新的、潜在的高效治疗方法，可以杀死转移性和/或化疗耐药的卵巢癌细胞。因此，本提案有三个相关的具体目的：1)表征claudin-3和-4在卵巢癌中的表达特征及其调控；2)表征卵巢癌细胞对cpe介导的细胞溶解的敏感性和耐药性；3)体内检查CPE治疗的药代动力学、疗效和毒性。该项目完成后，我们将迅速将这项研究转化为化疗耐药疾病患者的新型临床治疗方法。卵巢癌仍然是最致命的妇科恶性肿瘤，高达90%的晚期卵巢癌患者死于复发性化疗耐药肿瘤；因此，开发这种疾病的新疗法是改善公众健康的重中之重。拟议的研究结果将为快速临床转化一种创新的、潜在的高效治疗化疗耐药卵巢癌的方法奠定基础。

DESCRIPTION (provided by applicant): Ovarian carcinoma remains the cancer with the highest mortality rate among gynecological tumors. Although many ovarian cancer patients fully respond to the standard combination of surgery and chemotherapy, nearly 90% later develop recurrent chemotherapy-resistant cancer and inevitably succumb to their disease. Thus, development of innovative, effective therapies against recurrent/chemotherapy-resistant ovarian cancer remains a high priority for improving public health. Using high-throughput technologies to analyze genetic fingerprints of ovarian cancer, we have recently discovered extremely high expression of the genes encoding the proteins claudin-3 and claudin-4. Because claudin-3 and -4 are the epithelial receptors for Clostridium perfringens enterotoxin (CPE) and are sufficient to mediate CPE binding, which triggers subsequent toxin-mediated cytolysis, we hypothesize that using CPE to target ovarian cancer cells based on their high levels of claudin-3 and -4 is potentially a novel, highly effective therapeutic approach for chemotherapy-resistant ovarian cancer. Consistent with this view, we introduced CPE to cells cultured from several primary, metastatic, and chemotherapy-resistant ovarian cancers that overexpress claudin-3 and -4, and we found that these tumor cells, unlike healthy human tissues, are highly sensitive to CPE-mediated cytolysis. More importantly, we found that intraperitoneal CPE therapy in SCID mouse xenografts harboring a highly relevant clinical model of chemotherapy-resistant human ovarian cancer inhibited tumor growth in 100% of mice harboring 1-week established disease. Thus, using CPE to target the high levels of claudin-3 and -4 may represent an innovative, potentially highly effective therapeutic approach to kill metastatic and/or chemotherapy-resistant ovarian cancer cells. Accordingly, this proposal has three related specific aims: 1) Characterize profiles and regulation of expression of claudin-3 and -4 in ovarian cancer; 2) Characterize sensitivity and resistance of ovarian cancer cells to CPE-mediated cytolysis; and 3) Examine in vivo the pharmacokinetics, efficacy, and toxicity of CPE therapy. Upon completion of this project, we will be positioned to quickly translate this research into a novel clinical treatment for patients with chemotherapy-resistant disease. Ovarian carcinoma remains the most lethal of gynecologic malignancies, with up to 90% of patients diagnosed with advanced stage ovarian cancer dying from recurrent chemotherapy-resistant tumors; therefore, development of novel therapies for this disease is a high priority for improving public health. Results of the proposed research will lay the foundation for rapid clinical translation of an innovative, potentially highly effective treatment for patients with chemotherapy-resistant ovarian cancer.