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) 是第四大最常见的癌症死亡形式 美国的女性。 美国大约每 70 名女性中就有 1 人会 开发OC；在疾病晚期，患者的生存期为 5 年 约15-20%。 目前治疗晚期 OC 的方法并不 有效且晚期患者的复发率 高的。 Pivitol Biosciences 已证明肽 Contortrostatin (CN) 抑制人卵巢癌（OVCAR-5 细胞）的生长和扩散 动物模型。 使用鸡胚绒毛尿囊膜 (CAM) 模型 系统中，CN 阻断肿瘤细胞扩散并抑制诱导的血管生成 由 OVCAR-5 细胞。 因此，CN对卵巢癌有两管齐下的进攻， 阻止肿瘤的植入和血流以防止转移。 我们的 CN 抗癌活性的临床前研究表明 这种化合物是一种有前途的 OC 治疗新疗法。 作为下一步 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 腹腔内，通过腹膜内 (i.p.) 注射局部输送 CN 施用这种抗癌剂的可行方法。 我们已经 表明 ip。 CN 给药可抑制 OVCAR-5 的进展 动物体内。 在这个提案中，我们将测试是否将 CN 与 胶体金或使用 脂质体递送系统为 CN 提供最佳的抗癌活性。 我们 将测试这些制剂是否保持其抗血管生成作用 治疗 OC 的有效性。 该提案将为 未来研究（二期申请）以完成临床前开发 CN，以便可以提交 IND 在人类癌症患者中测试 CN。 拟议的商业应用： 抗血管生成疗法为癌症的治疗提供了重要的希望。然而，尚未有抗血管生成剂被批准用于临床。从理论上讲，这种形式的抗癌治疗有很多优点：它没有细胞毒性，并且不应受到获得性耐药性的限制。我们正在研究的药物 Contortrostatin 的独特之处在于它可以抑制肿瘤细胞的进展以及血管生成。将Concontrostatin靶向肿瘤部位的能力将显着增强其转化潜力。尽管该提案针对的是卵巢癌，但这种疗法应该广泛适用于多种癌症。到 2005 年，癌症抗血管生成治疗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