Enabling the repurposing of niclosamide for castrate-resistant prostate cancer using a novel formulation technology platform
使用新型制剂技术平台实现氯硝柳胺的再利用,用于治疗去势抵抗性前列腺癌
基本信息
- 批准号:10010726
- 负责人:
- 金额:$ 26.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:Advanced Malignant NeoplasmAffectAndrogen ReceptorAndrogensAntineoplastic AgentsAttentionBiological AvailabilityCancer BiologyCancer Cell GrowthCastrationCessation of lifeDataDevelopmentDiseaseDisease-Free SurvivalDosage FormsDoseDrug Delivery SystemsDrug KineticsDrug ScreeningFDA approvedFeasibility StudiesFormulationFutureGastrointestinal tract structureGenerationsGoalsIn VitroIndividualKineticsKnowledgeLeadLegal patentLinkLiteratureMalignant neoplasm of prostateMaximum Tolerated DoseMusNew AgentsOralOral AdministrationPatientsPerformancePharmaceutical PreparationsPhasePhase I Clinical TrialsPlayProgression-Free SurvivalsPropertyProstate Cancer therapyRNA SplicingReceptor SignalingReportingResearchResistanceRodent ModelRoleSolubilityTechniquesTechnologyTestingTherapeuticToxic effectUnited StatesVariantWaterXenograft procedureabirateroneabsorptionamorphous solidanalogatovaquonebasecancer diagnosiscancer therapycastration resistant prostate cancerdesigndrug efficacyefficacy studyhelminth infectionhigh throughput screeningimprovedin vivoinhibitor/antagonistlipophilicitymenmortalitymouse modelnext generationnovelphase 1 studyprogramsprostate cancer cellprotein expressionresearch clinical testingsafety testingsubcutaneoustumor growthwater solubility
项目摘要
Prostate cancer is the most common diagnosed cancer developing in men, developing in around 160,000 men
in the United States. While many men are successfully treated of the disease, nearly 30,000 continue to die
each year to do an advanced cancer which continues to grow despite castration levels of androgen present. A
new generation of androgen receptor signal inhibitors has come to the market and successfully improved the
survival of patients. However, resistance to the new agents is inevitable and occurs in the first few years after
beginning treatment. The resistance has been shown to be linked to splice variants in the androgen receptor.
Niclosamide has recently been discovered to inhibit at least splice variant expression AR-V7, which in
combination with next generation androgen receptor signal inhibitors has shown a synergistic effect. In a
recent phase I feasibility study however, niclosamide failed as a therapeutic due to bioavailability limitations.
Niclosamide is poorly water-soluble drugs who would benefit from our formulation design and processing
technology platform which improves upon current amorphous solid dispersions, the technique currently used in
19 FDA approved products. Preliminary evidence presence promising results for improvements in the drugs
bioavailability with this formulation technique. We propose to optimize the formulation through a quality by
design approach to maximize the performance of the drug in the formulation platform. After validating the
performance of niclosamide with our formulation platform with a pharmacokinetic study we will perform an
efficacy study in a subcutaneous xenograft mouse model of castration-resistant prostate cancer to support the
efficacy of the drug in feasible doses for future clinical testing.
前列腺癌是男性最常见的癌症,大约有160,000名男性
在美国。虽然许多男人成功治疗了这种疾病,但近30,000人继续死亡
每年都会进行晚期癌症,尽管存在cast割雄激素,但仍会继续增长。一个
新一代的雄激素受体信号抑制剂已进入市场,并成功改善了
患者的生存。但是,对新代理商的抵抗是不可避免的,并且发生在此后的头几年
开始治疗。该电阻已显示与雄激素受体中的剪接变体有关。
最近发现烟酰胺抑制至少剪接变体表达AR-V7,这在
结合下一代雄激素受体信号抑制剂已显示出协同作用。在
然而,最近的I期可行性研究,由于生物利用度的限制,烟酰胺失败了。
烟酰胺是水溶性不佳的药物,他们将从我们的配方设计和加工中受益
技术平台可改善当前的无定形固体分散体,目前使用的技术
19 FDA批准的产品。初步证据存在有望改善药物的结果
这种配方技术的生物利用度。我们建议通过质量优化配方
在配方平台中最大化药物性能的设计方法。验证后
通过我们的配方平台,通过药代动力学研究表现烟酰胺,我们将执行
在castration抗性前列腺癌的皮下异种移植小鼠模型中的功效研究以支持
该药物在可行剂量中的疗效用于将来的临床测试。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Robert O. Williams其他文献
Dissolution Enhancement of a Drug Exhibiting Thermal and Acidic Decomposition Characteristics by Fusion Processing: A Comparative Study of Hot Melt Extrusion and KinetiSol® Dispersing
通过熔融加工增强具有热分解和酸分解特性的药物的溶出度:热熔挤出和 KinetiSol® 分散的比较研究
- DOI:
- 发表时间:
2010 - 期刊:
- 影响因子:3.3
- 作者:
J. Hughey;James C Dinunzio;Ryan C. Bennett;Chris Brough;Dave A. Miller;Huaju Ma;Robert O. Williams;J. Mcginity - 通讯作者:
J. Mcginity
Evaluation of the USP dissolution test method A for enteric-coated articles by planar laser-induced fluorescence
- DOI:
10.1016/j.ijpharm.2006.08.047 - 发表时间:
2007-02-07 - 期刊:
- 影响因子:
- 作者:
Dave A. Miller;Mirko Gamba;Dorothea Sauer;Troy P. Purvis;Noel T. Clemens;Robert O. Williams - 通讯作者:
Robert O. Williams
Feasibility of intranasal delivery of thin-film freeze-dried monoclonal antibodies
薄膜冻干单克隆抗体鼻内递送的可行性
- DOI:
10.1101/2023.10.23.563139 - 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Yu;Haiyue Xu;K. AboulFotouh;Gerallt Williams;Julie Suman;Sawittree Sahakijpijarn;Chris Cano;Zachary N. Warnken;Kevin C.;Robert O. Williams;Zhengrong Cui - 通讯作者:
Zhengrong Cui
Compaction Properties of Microcrystalline Cellulose and Sodium Sulfathiazole in Combination with Talc or Magnesium Stearate
- DOI:
10.1002/jps.2600781211 - 发表时间:
1989-12-01 - 期刊:
- 影响因子:
- 作者:
Robert O. Williams;James W. McGinity - 通讯作者:
James W. McGinity
The Influence of Plasticizer on Heat-Humidity Curing of Cellulose Acetate Phthalate Coated Beads
增塑剂对邻苯二甲酸醋酸纤维素包覆微珠热湿固化的影响
- DOI:
10.1081/pdt-120000298 - 发表时间:
2001 - 期刊:
- 影响因子:3.4
- 作者:
Robert O. Williams;Jiping Liu - 通讯作者:
Jiping Liu
Robert O. Williams的其他文献
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