Targeted Therapy for Head and Neck Cancer
头颈癌的靶向治疗
基本信息
- 批准号:9764348
- 负责人:
- 金额:$ 36.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-15 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffinityAutomobile DrivingCancer ModelCancer PatientCell Culture TechniquesCell DeathCellsCessation of lifeClinical TrialsComputer SimulationDataDevelopmentDiseaseDisease ProgressionDoseDrug KineticsDrug Metabolic DetoxicationDrug TargetingElectronsEnzymesEvaluationFamily FelidaeFelis catusFundingGenerationsGleevecGoalsHead and Neck CancerHead and Neck Squamous Cell CarcinomaHumanHuman PathologyHydroquinonesIn VitroMalignant Epithelial CellMalignant NeoplasmsMediatingModelingModernizationMusMutationNQO1 geneNatural ProductsNormal tissue morphologyOutcomeOxidoreductaseParentsPatientsPharmaceutical PreparationsPopulationPre-Clinical ModelProcessProteinsQuinonesRadiationReactive Oxygen SpeciesRecurrenceSeriesStructure-Activity RelationshipTherapeuticTherapeutic IndexToxic effectTranslatingTrastuzumabVariantWorkXenograft ModelXenograft procedurebasebonebone invasioncancer cellcytotoxicdata reductiondesignexperimental studyhuman diseasein vivoinnovationmalignant breast neoplasmmelanomamouse modelnoveloutcome forecastoverexpressionpatient populationpatient responseresponsesmall moleculetargeted agenttargeted treatmenttranslation to humanstranslational modeltumortwo-arm study
项目摘要
Little progress has been made in the treatment of head-and-neck squamous cell carcinoma
(HNSCC) in decades, and there are no impactful targeted therapies for this deadly cancer. The
overexpression of the enzyme NQO1 has been observed in a high percentage of primary HNSCC tumors,
including in those HNSCC patients with the worst prognoses, and thus compounds that are toxified by NQO1
have the potential to induce marked tumor regression for a desperate patient population. We have obtained
a substantial amount of data showing the natural product deoxynyboquinone (DNQ) and its derivatives are
potently cytotoxic in cells that express NQO1. As NQO1 is elevated in HNSCC but has low expression in
normal tissue, DNQ and its derivatives have the potential as targeted drugs for HNSCC. In addition to
significant in vitro and cell culture data on DNQ and derivatives, we have also made pharmacokinetic,
toxicity, and efficacy assessments in mouse models of cancer and – excitingly – in pet cats with spontaneous
HNSCC. Feline HNSCC is very similar to the human disease and is regarded as a significantly more
representative and challenging pre-clinical model, thus our data showing activity of a DNQ derivative in
these pet cats with spontaneous HNSCC in a NQO1-dependent fashion is very promising. DNQ and its
derivatives we have identified thus far do not have the proper therapeutic index to become drugs, that is,
their NQO1-independent toxicity limits the dose that can be given to mice and cats in vivo. We have
experimentally ruled out various possibilities for the NQO1-independent cell death, and our experiments
suggest that this toxicity is mediated by the reduction of DNQ by the one-electron reductase P450R. Herein
we propose a comprehensive plan to widen the therapeutic index for DNQ and translate this drug class
toward human clinical trials. In Specific Aim 1 we use a combination of structure-activity relationships and
in silico modeling to design 80 novel DNQ derivatives that are predicted to be worse substrates for P450R
without compromising their NQO1 activity. These compounds will be moved through a tiered series of cell
culture, and patient-derived xenograft (Specific Aim 2) experiments, with the top compounds being
evaluated in pet cats with HNSCC in Specific Aim 3. Our goal is to have identified a derivative suitable for
translation to human clinical trials by the end of the funding period. This tightly-focused, hypothesis-driven
proposal could provide the first impactful targeted therapy for HNSCC; this would be a major breakthrough
for this vastly underserved patient population.
头颈部鳞状细胞癌的治疗进展甚微
(HNSCC)几十年来,对于这种致命的癌症没有有效的靶向治疗。的
已经在高百分比的原发性HNSCC肿瘤中观察到NQO 1酶的过表达,
包括在那些具有最严重疾病的HNSCC患者中,
对于绝望的患者群体来说,有可能诱导显著的肿瘤消退。我们所获得
大量的数据表明,天然产物脱氧尼波醌(DNQ)及其衍生物,
在表达NQO 1的细胞中具有强效细胞毒性。由于NQO 1在HNSCC中升高,但在HNSCC中表达较低,
正常组织中,DNQ及其衍生物具有作为HNSCC靶向药物的潜力。除了
关于DNQ和衍生物的重要的体外和细胞培养数据,我们还进行了药代动力学,
在小鼠癌症模型中的毒性和有效性评估,以及令人兴奋的是,
HNSCC。猫HNSCC与人类疾病非常相似,被认为是一种明显更严重的疾病。
代表性和挑战性的临床前模型,因此我们的数据显示DNQ衍生物在
这些宠物猫以NQO 1依赖的方式患有自发性HNSCC是非常有希望的。DNQ及其
迄今为止我们鉴定的衍生物不具有成为药物的适当治疗指数,也就是说,
它们的NQO 1非依赖性毒性限制了可给予小鼠和猫体内的剂量。我们有
实验排除了NQO 1独立细胞死亡的各种可能性,我们的实验
表明这种毒性是由单电子还原酶P450 R还原DNQ介导的。本文
我们提出了一个全面的计划,以扩大DNQ的治疗指数,
进行人体临床试验在具体目标1中,我们使用结构-活性关系的组合,
通过计算机模拟设计80种新的DNQ衍生物,这些衍生物预计是P450 R的较差底物
而不影响它们的NQO 1活性。这些化合物将通过一系列分层的细胞
培养和患者来源的异种移植物(特定目标2)实验,其中最高的化合物是
在特定目标3中对患有HNSCC的宠物猫进行了评价。我们的目标是找到一种适合
在资助期结束前转化为人体临床试验。这种高度集中的假设驱动的
该提案可以为HNSCC提供第一个有效的靶向治疗;这将是一个重大突破
为这一严重缺乏医疗服务的患者群体服务。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Paul Hergenrother其他文献
Paul Hergenrother的其他文献
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{{ truncateString('Paul Hergenrother', 18)}}的其他基金
FabI Inhibitors as Potent, Gut Microbiome-Sparing Antibiotics
FabI 抑制剂是有效的、保护肠道微生物群的抗生素
- 批准号:
10673319 - 财政年份:2023
- 资助金额:
$ 36.74万 - 项目类别:
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- 批准号:
10202668 - 财政年份:2020
- 资助金额:
$ 36.74万 - 项目类别:
Training Program at the Chemistry Biology Interface
化学生物学接口的培训计划
- 批准号:
10623229 - 财政年份:2020
- 资助金额:
$ 36.74万 - 项目类别:
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化学生物学接口的培训计划
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10441373 - 财政年份:2020
- 资助金额:
$ 36.74万 - 项目类别:
Predictive Guidelines for Penetrance and Discovery of Broad-Spectrum Antibiotics
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- 批准号:
10326787 - 财政年份:2018
- 资助金额:
$ 36.74万 - 项目类别:
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