Targeting PCSK9 axis for castration-resistant prostate cancer recurrence suppression

摘要 转移性去势抵抗前列腺癌(MCRPC)是复发率最高、致死率最高的肿瘤。 表型。MCRPC患者无复发能力差，预防措施有限。这个 天然产物Pseurotin A(PS)对PCSK9的分泌和与LDLR的相互作用具有双重抑制作用。 PS对裸鼠模型中94%的PC-3PC复发有抑制作用。多糖硫酸酯抗迁移活性 当PCSK9被推倒时，显著减少。PS的小分子尺寸是 优于FDA批准的作用于细胞内外的人源化PCSK9单抗 与后者不同，后者只能作用于细胞外，反映出更好的效力。最近，PCSK9 事实证明，它是前列腺癌和其他几种癌症的关键驱动力。项目中心假设是 小分子PCSK9抑制剂靶向细胞内外PCSK9轴 Pseurotin A能有效防止mCRPC复发，因此PS可以 成为mCRPC存活者有效的复发预防药物。目标1：PS的疗效 PCSK9在裸鼠体内预防mCRPC复发及其作为发病机制标志物的验证 人PC组织微阵列。评估将比较野生和PCSK9中的PS效力- 在辅助(原发肿瘤切除后)模式下和之后击倒CWR-R1ca细胞 新辅助苯舒他胺-多西紫杉醇联合裸鼠原发肿瘤手术切除 小鼠模型。Biomax人体组织微阵列将用于验证PCSK9的相关性 人类个人电脑。目的2：评价PS在瑞士白化小鼠模型中的安全性和药代动力学。 预期结果：拟议的研究需要PS作为一种新的有针对性的干预措施 预防mCRPC复发。PCSK9靶向治疗是一种新的长期治疗方案 前列腺癌抗去势转移复发的预防 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.