TREATMENT OF OVARIAN CANCER WITH CONTORTROSTATIN

用 CONTROSTATIN 治疗卵巢癌

• 批准号: 6292335
• 负责人: FRANCIS S MARKLAND
• 金额: $ 20.72万
• 依托单位: PIVOTAL BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-11 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6292335
• 关键词: angiogenesis; angiogenesis inhibitors; athymic mouse; biotherapeutic agent; chick embryo; drug design /synthesis /production; female; gene delivery system; immunocytochemistry; liposomes; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; ovary neoplasms; peptides; xenotransplantation

DESCRIPTION: (Applicant's Description) Ovarian carcinoma (OC) is the fourth most frequent form of cancer death of women in the United States. Approximately 1 in 70 women in the US will develop OC; in advanced stages of the disease there is a 5-year survival of about 15-20%. Present methods of treatment for advanced stage OC are not effective and the recurrence rate in patients with advanced stage disease is high. Pivitol Biosciences has shown that the peptide contortrostatin (CN) inhibited growth and dissemination of human ovarian cancer (OVCAR-5 cells) in an animal model. Using the chick embryo chorioallantoic membrane (CAM) model system, CN blocked tumor cell dissemination and inhibited angiogenesis induced by OVCAR-5 cells. Thus, CN has a two pronged attack on ovarian cancer, it blocks implantation and blood flow to the tumors to prevent metastasis. Our pre-clinical investigations on the anti-cancer activities of CN indicate that this compound is a promising new therapy for OC. As a next step in the pre-clinical development of CN, in this proposal, we will determine the optimal formulations of CN to treat OC. Since OC disseminates inside the peritoneal cavity, local delivery of CN by intraperitoneal (i.p.) injection is a feasible approach for administering this anticancer agent. We have already shown that i.p. administration of CN can inhibit progression of OVCAR-5 in vivo in animals. In this proposal we will test whether conjugating CN with colloidal gold or developing a sustained release formulation of CN using a liposome delivery system provides optimal anti-cancer activity for CN. We will test whether these formulations maintain their anti-angiogenic effectiveness in treating OC. This proposal will establish the foundation for future studies (phase II application) to complete the pre-clinical development of CN so that an IND can be filed to test CN in human cancer patients. PROPOSED COMMERCIAL APPLICATIONS: Antiangiogenic therapy offers significant promise for the treatment of cancer. However, no antiangiogenic agent has yet been approved for clinical use. Theoretically, this form of anticancer therapy has many advantages: it is not cytotoxic and should not be limited by acquired drug resistance. The agent we are investigating, contortrostatin, is unique in that it inhibits both tumor cell progression as well as angiogenesis. The ability to target contortrostatin to the tumor site will significantly enhance its translational potential. Although this proposal targets ovarian cancer, this form of therapy should be widely applicable for many forms of cancer. The potential market for cancer antiangiogenic therapy could approach $3 billion by 2005.

描述：（申请人的描述） 卵巢癌（OC）是癌症死亡的第四大常见形式， 美国的女性。 在美国，每70名女性中就有1名 发展OC;在疾病的晚期， 大约15- 20%。 目前治疗晚期OC的方法不是 有效，晚期疾病患者的复发率为 高 Pivitol Biosciences已经表明，肽contortrostatin（CN） 抑制人卵巢癌（OVCAR-5细胞）在 动物模型。 采用鸡胚绒毛尿囊膜（CAM）模型 系统，CN阻断肿瘤细胞播散并抑制诱导的血管生成 OVCAR-5细胞 因此，CN对卵巢癌有双管齐下的攻击， 阻断移植和流向肿瘤的血流以防止转移。 我们 CN抗癌活性的临床前研究表明， 该化合物是一种有前途的治疗OC的新方法。 作为 CN的临床前开发，在本提案中，我们将确定 CN治疗OC的最佳配方。 由于OC在内部传播 腹膜腔，通过腹膜内（i. p.）喷射 一种可行的给予该抗癌剂的方法。 我们已经 显示腹膜内给予CN可抑制OVCAR-5在 在动物体内。 在这个建议中，我们将测试是否共轭CN与 胶体金或开发氯化萘的缓释制剂， 脂质体递送系统提供CN的最佳抗癌活性。 我们 将测试这些配方是否保持其抗血管生成 有效治疗OC。 该提案将为以下方面奠定基础： 完成临床前开发的未来研究（II期申请） 这样就可以申请IND来测试人类癌症患者的CN。 拟议的商业应用： 抗血管生成治疗为癌症的治疗提供了重要的前景。然而，还没有抗血管生成剂被批准用于临床使用。从理论上讲，这种形式的抗癌疗法有许多优点：它没有细胞毒性，不应受到获得性耐药性的限制。我们正在研究的药物，contortrostatin，是独特的，因为它抑制肿瘤细胞的进展以及血管生成。将contortrostatin靶向肿瘤部位的能力将显著增强其翻译潜力。虽然这一建议针对卵巢癌，但这种形式的治疗应该广泛适用于许多形式的癌症。到2005年，癌症抗血管生成疗法的潜在市场可能接近30亿美元。

项目成果

Action of fenretinide (4-HPR) on ovarian cancer and endothelial cells.

• 发表时间: 2005
• 期刊: Anticancer research
• 影响因子: 2
• 作者: V. Golubkov;Agustin Garcia;F. Markland

Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression.

• DOI: 10.1158/1535-7163.499.3.4
• 发表时间: 2004-04
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: S. Swenson;Fritz K. Costa;R. Minea;R. Sherwin;W. Ernst;G. Fujii;Dongyun Yang;F. Markland