Targeting PCSK9 axis for castration-resistant prostate cancer recurrence suppression

靶向 PCSK9 轴抑制去势抵抗性前列腺癌复发

• 批准号: 10429627
• 负责人: KHALID A EL SAYED
• 金额: $ 18.24万
• 依托单位: UNIVERSITY OF LOUISIANA AT MONROE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429627
• 关键词: Acute; Adjuvant; Advocate; Agonist; Androgen Antagonists; Androgen Receptor; Androgen Suppression; Aspergillus fumigatus; Automobile Driving; Biological Availability; Blood specimen; Cancer Patient; Cancer Relapse; Cell Surface Receptors; Cells; Cholesterol; Chronic; Clinical; Clinical Pathology; Data; Disease; Dose; Drug Controls; Drug Kinetics; Excision; FDA approved; Fermentation; Follicle Stimulating Hormone; Histopathology; Human; Immunotherapy; Individual; Intervention; KDR gene; LDL Cholesterol Lipoproteins; Lactams; Lead; Link; Lipids; Low Density Lipoprotein Receptor; Luteinization; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Metastatic Prostate Cancer; Monoclonal Antibodies; Mus; Natural Products; Neoadjuvant Therapy; Neoplasm Metastasis; Nude Mice; Obesity; Operative Surgical Procedures; Oral; Organ; Outcome; PECAM1 gene; PTK2 gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Premalignant Cell; Prevention; Preventive; Primary Neoplasm; Proprotein Convertases; Prostate; Publishing; Recurrence; Regimen; Resistance; Resistance development; Role; Safety; Slide; Staging; Stains; Subtilisins; Survival Rate; Survivors; Testing; Testosterone; Tissue Microarray; Validation; Western Blotting; albino mouse; angiogenesis; animal imaging; cancer cell; cancer clinical trial; cancer recurrence; castration resistant prostate cancer; cell motility; chemotherapy; cholesterol biosynthesis; cost; disorder later incidence prevention; docetaxel; effective therapy; enzalutamide; extracellular; fungus; hormone therapy; human tissue; hypercholesterolemia; inhibitor; knock-down; malignant breast neoplasm; men; microbial; molecular size; mortality; mouse model; neoplastic cell; novel; novel therapeutics; paxillin; preclinical study; prevent; prospective; prostate cancer cell; prostate cancer metastasis; prostate cancer prevention; prostate cancer progression; prostate cancer survivors; protein protein interaction; receptor expression; selective androgen receptor modulator; serum PSA; side effect; small molecule; tumor; uptake

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.

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