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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.

概括转移性去势抵抗性前列腺癌 (mCRPC) 是最容易复发且致命的癌症表型。 mCRPC 患者的无复发率较差且预防选择有限。这天然产物 pseurotin A (PS) 双重抑制 PCSK9 分泌以及与 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 PCSK9 被敲低时，其显着降低。 PS的小分子尺寸为优于 FDA 批准的细胞内和细胞外作用的人源化 PCSK9 mAb 与后者不同，后者只能在细胞外起作用，反映了更好的效力。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因素。项目中心假设是使用小分子 PCSK9 抑制剂靶向细胞外和细胞内 PCSK9 轴 pseurotin A 可以有效预防 mCRPC 复发，因此 PS 可以开发为 mCRPC 幸存者的有效复发预防剂。目标 1：PS 的功效预防裸鼠 mCRPC 复发以及 PCSK9 作为发病机制标志物的验证人类PC组织微阵列。评估将比较野生和 PCSK9- 中的 PS 效力在辅助（原发性肿瘤切除后）模式和之后敲低 CWR-R1ca 细胞新辅助恩佐他胺-多西紫杉醇方案随后进行裸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 的相关性人类电脑。目标 2：评估瑞士白化小鼠模型中的 PS 安全性和药代动力学。预期结果：拟议的研究需要将 PS 验证作为一种新颖的有针对性的干预措施预防 mCRPC 复发。 PCSK9 靶向是一种新型的长期治疗替代方案预防前列腺癌转移性去势抵抗性前列腺癌复发幸存者。

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.