Targeting PCSK9 axis for castration-resistant prostate cancer recurrence suppression

总结 转移性去势抵抗性前列腺癌（mCRPC）是最复发和致命的 表型mCRPC患者的无复发性较差，预防选择有限。的 天然产物pseurotin A（PS）双重抑制PCSK 9分泌和与LDLR的相互作用。 在裸鼠模型中，PS抑制了94%的PC-3 PC复发。PS抗迁移活性 当PCSK 9被敲除时显著降低。PS的小分子尺寸是 与FDA批准的人源化PCSK 9 mAb相比， 不像后者，后者只能在细胞外起作用，反映出更好的效力。近日，PCSK 9 被证明是前列腺癌和其他几种癌症的关键驱动因素。项目中心假设是 用小分子PCSK 9抑制剂靶向细胞外和细胞内PCSK 9轴 Pseurotin A可有效预防mCRPC复发，因此PS可 在mCRPC幸存者中开发为有效的复发预防剂。目的1：PS对 在裸鼠中预防mCRPC复发，并验证PCSK 9作为 人PC组织微阵列。评估将比较野生型和PCSK 9- 在佐剂（原发性肿瘤切除后）模式中以及在 新辅助恩祖利韦-多西他赛方案，随后进行裸原发性肿瘤手术切除 小鼠模型。Biomax人体组织微阵列将用于验证PCSK 9与 人类电脑目的2：评估PS在瑞士白化病小鼠模型中的安全性和药代动力学。 预期结果：拟定的研究需要PS验证作为一种新的靶向干预， 预防mCRPC复发。PCSK 9靶向是一种新的长期治疗选择， 前列腺癌中转移性去势抵抗性前列腺癌复发的预防 幸存者

SUMMARY Metastatic castration-resistant prostate cancer (mCRPC) is the most recurrent and, fatal phenotype. mCRPC patients have poor recurrence-free and limited preventive options. The natural product pseurotin A (PS) dually suppressed PCSK9 secretion and interaction with LDLR. PS suppressed 94% of PC-3 PC recurrence in nude mice model. PS antimigratory activity significantly reduced when PCSK9 knocked-down. The small molecular size of PS is advantageous over the FDA-approved humanized PCSK9 mAbs acting intra- and extra-cellular unlike the later which can act extracellular only, reflecting better potency. Recently, PCSK9 proved critical driver for prostate and several other cancers. Project central hypothesis is targeting extra- and intracellular PCSK9 axis with the small molecule PCSK9 inhibitor pseurotin A can effectively prevent mCRPC recurrences and therefore PS can be developed as effective recurrence preventer in mCRPC survivors. Aim 1: Efficacy of PS to prevent mCRPC recurrence in nude mice and PCSK9 validation as a pathogenesis marker in human PC tissues microarray. Assessments will compare PS potency in wild and PCSK9- knockdown CWR-R1ca cells in adjuvant (post-primary tumor excision) mode and after neoadjuvant enzultamide- docetaxel regimen followed by primary tumor surgical excision in nude mice models. Biomax human tissue microarray will be used to validate PCSK9 relevance in human PC. Aim 2: Assess the PS safety and pharmacokinetics in Swiss albino mouse models. Expected outcomes: Proposed studies entail PS validation as a novel targeted intervention for mCRPC recurrences prevention. PCSK9 targeting is a novel therapeutic alternative for long-term prevention of metastatic castration-resistant prostate cancer recurrence in prostate cancer survivors.