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

前列腺癌是男性最常见的确诊癌症，约有16万人罹患前列腺癌 在美国。虽然许多男性成功地治疗了这种疾病，但仍有近30,000人死亡 每年都要做一种晚期癌症，尽管目前存在去势的雄激素水平，这种癌症仍在继续增长。一个 新一代雄激素受体信号抑制剂已上市，并成功改善了 病人的生存。然而，对新药物的抗药性是不可避免的，并发生在之后的头几年 开始治疗。这种耐药性已被证明与雄激素受体的剪接变体有关。 氯硝柳胺最近被发现至少可以抑制AR-V7的剪接变异体表达，它在 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，最近的第一阶段可行性研究，由于生物利用度的限制，氯硝柳胺作为一种治疗药物失败。 氯硝柳胺是难于溶于水的药物，可从我们的处方设计和加工中受益 改进目前无定形固体分散体的技术平台，目前使用的技术 19种FDA批准的产品。初步证据表明，这些药物的改进效果令人振奋 该制剂技术的生物利用度。我们建议通过以下方式来优化配方： 设计方法使药物在配方平台中的性能最大化。在验证了 氯硝柳胺在我们的制剂平台上的性能通过药代动力学研究，我们将进行 小鼠皮下移植耐去势前列腺癌模型支持去势前列腺癌的疗效研究 该药物在可行剂量下的疗效可用于未来的临床试验。

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.