Targeting PCSK9 axis for castration-resistant prostate cancer recurrence suppression
Targeting PCSK9 axis for castration-resistant prostate cancer recurrence suppression
批准号:
10429627
负责人:
KHALID A EL SAYED
金额:
$18.24万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-03-01 至 2024-02-29
关键词:
AcuteAdjuvantAdvocateAgonistAndrogen AntagonistsAndrogen ReceptorAndrogen SuppressionAspergillus fumigatusAutomobile DrivingBiological AvailabilityBlood specimenCancer PatientCancer RelapseCell Surface ReceptorsCellsCholesterolChronicClinicalClinical PathologyDataDiseaseDoseDrug ControlsDrug KineticsExcisionFDA approvedFermentationFollicle Stimulating HormoneHistopathologyHumanImmunotherapyIndividualInterventionKDR geneLDL Cholesterol LipoproteinsLactamsLeadLinkLipidsLow Density Lipoprotein ReceptorLuteinizationMalignant NeoplasmsMalignant neoplasm of prostateMeasuresMetastatic Prostate CancerMonoclonal AntibodiesMusNatural ProductsNeoadjuvant TherapyNeoplasm MetastasisNude MiceObesityOperative Surgical ProceduresOralOrganOutcomePECAM1 genePTK2 genePathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhenotypePremalignant CellPreventionPreventivePrimary NeoplasmProprotein ConvertasesProstatePublishingRecurrenceRegimenResistanceResistance developmentRoleSafetySlideStagingStainsSubtilisinsSurvival RateSurvivorsTestingTestosteroneTissue MicroarrayValidationWestern Blottingalbino mouseangiogenesisanimal imagingcancer cellcancer clinical trialcancer recurrencecastration resistant prostate cancercell motilitychemotherapycholesterol biosynthesiscostdisorder later incidence preventiondocetaxeleffective therapyenzalutamideextracellularfungushormone therapyhuman tissuehypercholesterolemiainhibitorknock-downmalignant breast neoplasmmenmicrobialmolecular sizemortalitymouse modelneoplastic cellnovelnovel therapeuticspaxillinpreclinical studypreventprospectiveprostate cancer cellprostate cancer metastasisprostate cancer preventionprostate cancer progressionprostate cancer survivorsprotein protein interactionreceptor expressionselective androgen receptor modulatorserum PSAside effectsmall moleculetumoruptake
中文摘要
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。
英文摘要
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.
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会议论文
Targeting PCSK9 axis for castration-resistant prostate cancer recurrence suppression
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