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

CPE 治疗化疗耐药的人类卵巢癌

• 批准号: 7369939
• 负责人: Alessandro D Santin
• 金额: $ 34.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7369939
• 关键词: Animals; Binding; Biological; Cancer Patient; Cancer cell line; Cell Line; Cell Therapy; Cell surface; Cells; Clinical; Clinical Treatment; Clinical Trials; Clostridium enterotoxin; Clostridium perfringens enterotoxin; Clostridium perfringens enterotoxin receptor; Cultured Cells; Cytolysis; DNA Methylation; Data; Development; Diagnosis; Disease; Disease Resistance; Dose; Dose-Limiting; Drug Kinetics; Drug or chemical Tissue Distribution; Epigenetic Process; Epithelial; Epithelial Cells; Excretory function; Fingerprint; Foundations; Future; Gene Expression; Genes; Goals; Gynecologic; Histology; Histones; Human; Immunohistochemistry; In Vitro; Intraperitoneal Injections; Intravenous; Label; Length; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mesothelial Cell; Messenger RNA; Modeling; Modification; Molecular Profiling; Molecular Target; Mus; Neoplasm Metastasis; Numbers; Oligonucleotide Microarrays; Operative Surgical Procedures; Organ; OspC protein; Ovarian; Ovarian Carcinoma; Ovarian Diseases; Papillary Neoplasm; Patients; Peptides; Permeability; Plasma; Play; Polymerase Chain Reaction; Positioning Attribute; Promoter Regions; Protein Overexpression; Proteins; Public Health; Rate; Recurrence; Regulation; Research; Resistance; Role; SCID Mice; Serous; Staging; Standards of Weights and Measures; Surface; Testing; Therapeutic; Therapeutic Effect; Tight Junctions; Time; Toxic effect; Toxin; Transcriptional Regulation; Translating; Translations; Week; Xenograft Model; Xenograft procedure; base; cancer cell; chemotherapy; claudin 3; claudin 4; clinically relevant; clinically significant; cytotoxicity; design; experience; genetic analysis; high throughput technology; human tissue; improved; in vivo; innovation; intraperitoneal; intravenous administration; killings; mortality; mouse model; neoplastic cell; novel; novel strategies; ovarian neoplasm; preclinical study; prevent; promoter; receptor; research study; tumor; tumor growth; tumorigenesis

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.

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反应，但近 90% 的患者后来发展为复发性化疗耐药性癌症，并不可避免地死于疾病。因此，针对复发性/化疗耐药性卵巢癌开发创新、有效的疗法仍然是改善公众健康的重中之重。利用高通量技术分析卵巢癌的遗传指纹，我们最近发现编码蛋白质claudin-3和claudin-4的基因极高表达。由于 Claudin-3 和 -4 是产气荚膜梭菌肠毒素 (CPE) 的上皮受体，并且足以介导 CPE 结合，从而引发随后的毒素介导的细胞溶解，因此我们假设，基于高水平的 Claudin-3 和 -4，使用 CPE 靶向卵巢癌细胞可能是一种新型、高效的化疗耐药治疗方法。 卵巢癌。与这一观点一致，我们将CPE引入从几种原发性、转移性和化疗耐药性卵巢癌中过度表达claudin-3和-4培养的细胞中，我们发现这些肿瘤细胞与健康人体组织不同，对CPE介导的细胞溶解高度敏感。更重要的是，我们发现，对具有高度相关的化疗耐药性人类卵巢癌临床模型的 SCID 小鼠异种移植物进行腹腔内 CPE 治疗，可 100% 抑制 1 周已患病小鼠的肿瘤生长。因此，使用 CPE 靶向高水平的claudin-3和-4可能代表一种创新的、潜在高效的治疗方法来杀死转移性和/或化疗耐药的卵巢癌细胞。因此，该提案具有三个相关的具体目标：1）表征卵巢癌中claudin-3和-4表达的概况和调节； 2）表征卵巢癌细胞对CPE介导的细胞溶解作用的敏感性和抵抗力； 3) 检查 CPE 疗法的体内药代动力学、功效和毒性。该项目完成后，我们将能够迅速将这项研究转化为针对化疗耐药性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，开发针对这种疾病的新疗法是改善公众健康的当务之急。拟议研究的结果将为针对化疗耐药性卵巢癌患者的创新、潜在高效治疗方法的快速临床转化奠定基础。