Enabling the repurposing of niclosamide for castrate-resistant prostate cancer using a novel formulation technology platform

使用新型制剂技术平台实现氯硝柳胺的再利用，用于治疗去势抵抗性前列腺癌

• 批准号: 10010726
• 负责人: Robert O. Williams
• 金额: $ 26.39万
• 依托单位: VIA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010726
• 关键词: Advanced Malignant Neoplasm; Affect; Androgen Receptor; Androgens; Antineoplastic Agents; Attention; Biological Availability; Cancer Biology; Cancer Cell Growth; Castration; Cessation of life; Data; Development; Disease; Disease-Free Survival; Dosage Forms; Dose; Drug Delivery Systems; Drug Kinetics; Drug Screening; FDA approved; Feasibility Studies; Formulation; Future; Gastrointestinal tract structure; Generations; Goals; In Vitro; Individual; Kinetics; Knowledge; Lead; Legal patent; Link; Literature; Malignant neoplasm of prostate; Maximum Tolerated Dose; Mus; New Agents; Oral; Oral Administration; Patients; Performance; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Play; Progression-Free Survivals; Property; Prostate Cancer therapy; RNA Splicing; Receptor Signaling; Reporting; Research; Resistance; Rodent Model; Role; Solubility; Techniques; Technology; Testing; Therapeutic; Toxic effect; United States; Variant; Water; Xenograft procedure; abiraterone; absorption; amorphous solid; analog; atovaquone; base; cancer diagnosis; cancer therapy; castration resistant prostate cancer; design; drug efficacy; efficacy study; helminth infection; high throughput screening; improved; in vivo; inhibitor/antagonist; lipophilicity; men; mortality; mouse model; next generation; novel; phase 1 study; programs; prostate cancer cell; protein expression; research clinical testing; safety testing; subcutaneous; tumor growth; water solubility

Prostate cancer is the most common diagnosed cancer developing in men, developing in around 160,000 men in the United States. While many men are successfully treated of the disease, nearly 30,000 continue to die each year to do an advanced cancer which continues to grow despite castration levels of androgen present. A new generation of androgen receptor signal inhibitors has come to the market and successfully improved the survival of patients. However, resistance to the new agents is inevitable and occurs in the first few years after beginning treatment. The resistance has been shown to be linked to splice variants in the androgen receptor. Niclosamide has recently been discovered to inhibit at least splice variant expression AR-V7, which in combination with next generation androgen receptor signal inhibitors has shown a synergistic effect. In a recent phase I feasibility study however, niclosamide failed as a therapeutic due to bioavailability limitations. Niclosamide is poorly water-soluble drugs who would benefit from our formulation design and processing technology platform which improves upon current amorphous solid dispersions, the technique currently used in 19 FDA approved products. Preliminary evidence presence promising results for improvements in the drugs bioavailability with this formulation technique. We propose to optimize the formulation through a quality by design approach to maximize the performance of the drug in the formulation platform. After validating the performance of niclosamide with our formulation platform with a pharmacokinetic study we will perform an efficacy study in a subcutaneous xenograft mouse model of castration-resistant prostate cancer to support the efficacy of the drug in feasible doses for future clinical testing.

前列腺癌是男性中最常见的诊断癌症，约有 160,000 名男性患有前列腺癌 在美国。虽然许多男性已成功治愈这种疾病，但仍有近 30,000 人死亡 每年都会做一种晚期癌症，尽管存在雄激素水平的去势，但癌症仍在继续生长。一个 新一代雄激素受体信号抑制剂上市，成功改善了 患者的生存。然而，对新药物的抵制是不可避免的，并且发生在新药物上市后的最初几年。 开始治疗。已证明这种抗性与雄激素受体中的剪接变体有关。 最近发现氯硝柳胺至少能抑制剪接变体表达 AR-V7，这在 与下一代雄激素受体信号抑制剂联合应用显示出协同效应。在一个 然而，最近的一期可行性研究中，由于生物利用度的限制，氯硝柳胺未能作为治疗药物。 氯硝柳胺是水溶性差的药物，将受益于我们的配方设计和加工 技术平台，改进了当前的无定形固体分散体，目前使用的技术 19种FDA批准的产品。初步证据显示药物改进有希望取得成果 该制剂技术的生物利用度。我们建议通过质量优化配方 设计方法以最大限度地发挥制剂平台中药物的性能。验证后 我们将通过药代动力学研究来评估氯硝柳胺在我们的制剂平台上的性能 去势抵抗性前列腺癌皮下异种移植小鼠模型的疗效研究支持 药物在可行剂量下的功效，以供未来的临床测试。