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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

基本信息

批准号：
10555260
负责人：
KHALID A EL SAYED
金额：
$ 16.15万
依托单位：
UNIVERSITY OF LOUISIANA AT MONROE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10555260
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 Chromatography 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 Recurrent Malignant Neoplasm Recurrent tumor 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 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 relapse prevention selective androgen receptor modulator serum PSA side effect small molecule targeted treatment tumor uptake validation studies

项目摘要

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

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pseurotin A Validation as a Metastatic Castration-Resistant Prostate Cancer Recurrence-Suppressing Lead via PCSK9-LDLR Axis Modulation.

DOI：
10.3390/md21040215
发表时间：
2023-03-28
期刊：
Marine drugs
影响因子：
5.4
作者：
通讯作者：

The Tobacco β-Cembrenediol: A Prostate Cancer Recurrence Suppressor Lead and Prospective Scaffold via Modulation of Indoleamine 2,3-Dioxygenase and Tryptophan Dioxygenase.

烟草β-环甲基二醇：前列腺癌复发抑制铅和前瞻性支架，通过调节吲哚胺2,3-二氧酶和色氨酸二氧酶。

DOI：
10.3390/nu14071505
发表时间：
2022-04-04
期刊：
NUTRIENTS
影响因子：
5.9
作者：
Mudhish, Ethar A.;Siddique, Abu Bakar;Ebrahim, Hassan Y.;Abdelwahed, Khaldoun S.;King, Judy Ann;El Sayed, Khalid A.
通讯作者：
El Sayed, Khalid A.

Towards Developing Novel Prostate Cancer Recurrence Suppressors: Acute Toxicity of Pseurotin A, an Orally Active PCSK9 Axis-Targeting Small-Molecule in Swiss Albino Mice.

DOI：
10.3390/molecules28031460
发表时间：
2023-02-02
期刊：
MOLECULES
影响因子：
4.6
作者：
McGehee, Oliver C.;Ebrahim, Hassan Y.;Rad, Ashkan H.;Abdelwahed, Khaldoun S.;Mudhish, Ethar A.;King, Judy A.;Helal, Iman E.;Meyer, Sharon A.;El Sayed, Khalid A.
通讯作者：
El Sayed, Khalid A.