基于细胞PK-PD模型与双靶标作用机制探索普克鲁胺抗前列腺癌的药效优势

Castrate resistant prostate cancer (CRPC) is the fatal-form of prostate cancer. In China, the treatment for CRPC was quite limited except for traditional chemotherapy or radiotherapy. Targeted therapy was urgently required for clinical application. GT0918 is an innovative drug developed in china for CRPC. It has the same core structure with MDV3100. MDV3100 is a potent antagonist targeting androgen receptor (AR) , and it was approved by FDA in 2012 for the treatment of patients with CRPC who have received prior docetaxel. However, during the previous research, the plasma exposure of GT0918 under the best effect was less than half of that under MDV3100,and the intervention on tumor cell growth was also quite different between GT0918 and MDV3100. Therefore, this study aims to re-interpret the relationship between concentration and effect by establishing a cell-targeted PK-PD binding model, elucidate the correlation between the differences in the cellular dynamic and that in the antitumor efficacy of GT0918 and MDV3100.This study would provide new ideas and methods for the development and screening of AR-targeted drugs. At the same time, one scientific hypothesis was proposed by the applicant that GT0918 might be more efficacious in CRPC through its dual activities as a CYP17A1 inhibitor and AR antagonist. By inhibiting CYP17A1 to reduce androgen synthesis, while down-regulation of AR expression and block AR signaling pathway, GT0918 would introduce multiple attacks on the recurrence of androgen axis in CRPC. A clear understanding of the molecular mechanism of GT0918 would be helpful to provide a scientific basis for its efficacy advantage and clinical application, which would alleviate the domestic difficulties on CRPC treatment. In addition, the study of the structure-activity relationship between GT0918 and MDV3100 would also promote the structural design and transformation of CRPC-targeted drugs.

去势抵抗性前列腺癌（CRPC）是晚期前列腺癌治疗的难点，除了传统的化疗和放疗，国内缺乏有效的靶向治疗药物。普克鲁胺是我国自主研发的口服CRPC治疗药物，它与国外上市的新型雄激素受体（AR）靶向抑制剂-恩杂鲁胺具有相同的核心结构，但其达到最佳药效时的血浆药物暴露量不足恩杂鲁胺的半数，且前期研究显示普克鲁胺对肿瘤细胞的干预方式区别于恩杂鲁胺。因此，本研究拟通过建立细胞靶向PK-PD结合模型重新诠释浓度与效应的关系，阐明普克鲁胺与恩杂鲁胺在肿瘤细胞内动态处置过程上的差异与药效差异的相关性，为AR靶向药物的开发与筛选提供新的研究思路与方法。其次，申请者提出科学假说：普克鲁胺具有CYP17A1和AR双靶标作用机制，通过抑制CYP17A1减少雄激素合成、下调AR表达、拮抗AR信号通路，多重打击雄激素轴在CRPC进程中的复发。而普克鲁胺与恩杂鲁胺之间的构效研究亦将推动CRPC靶向药物的结构设计与改造。

普克鲁胺是我国自主研发的新一代雄激素受体（AR）拮抗剂，其以恩杂鲁胺的母核为基础进行结构优化，拟适应症为去势抵抗性前列腺癌（CRPC），目前正在中美同时开展Ⅲ期临床研究。普克鲁胺的成功开发对国内CRPC的治疗具有重大的临床价值，其将填补国内CRPC治疗中无可适AR靶向药物的空白，打破国内晚期前列腺癌患者“无药可用”的困境。前期研究基础中已经发现普克鲁胺的药效优于恩杂鲁胺，但是这种药效优势并不能在传统的整体药代动力学研究中得到解释，因此本研究旨在从整体到细胞，从外在到内在多个维度探索普克鲁胺发挥药效优势的具体机制。本研究通过建立荷瘤鼠动物模型和人前列腺癌细胞模型，应用组织药代动力学、细胞药代动力学、非靶代谢组学、靶标性脂质代谢组学以及流式分选、免疫荧光、实时荧光定量PCR、免疫印迹等研究手段，从药代动力学（PK）和药效学（PD）两方面入手，一方面从组织水平和细胞水平探索普克鲁胺优于恩杂鲁胺的PK性质，结果发现普克鲁胺在靶器官（前列腺）和靶细胞器（细胞核）上的特异性分布和高浓度分布是普克鲁胺药效优于恩杂鲁胺的可能原因；另一方面从多靶点多角度的药效机制上探索普克鲁胺区别于恩杂鲁胺的PD性质，结果发现普克鲁胺有效干预肿瘤细胞的多种恶性生物学行为（增殖/凋亡/迁移），并对肿瘤细胞产生三重打击（抑制雄激素生物合成、减少雄激素受体数量、抑制AR信号传导），同时通过调控肿瘤细胞内源性代谢的脂质储备、核苷酸储备以及氧化还原稳态提高肿瘤细胞对药物干预的敏感性，最终产生优于恩杂鲁胺的理想药效。

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