RETINOID THERAPY
RETINOID THERAPY
批准号:
7901622
负责人:
CHARLES Patrick REYNOLDS
金额:
$24.75万
依托单位国家:
美国
项目类别:
财政年份:
--
资助国家:
美国
项目状态:
未结题
起止时间:
至
关键词:
AdultAnimal ModelAntioxidantsApoptosisAscorbic AcidBiological AssayBiological AvailabilityBiological ModelsBiologyCaspaseCell DeathCell LineCeramide glucosyltransferaseCeramidesChemicalsChildhoodClinicalClinical ResearchClinical TrialsComplementary DNACyclophosphamideDataDevelopmentDiseaseDominant-Negative MutationDoseDrug CombinationsDrug ExposureDrug FormulationsDrug KineticsEnzymesEstrogen ReceptorsEstrogensEventFenretinideFutureGlucosylceramidesGlutathioneGrantHumanImmunocompromised HostInjection of therapeutic agentIntravenousIntravenous infusion proceduresIsotretinoinMYCN geneMalignant NeoplasmsMediatingMolecularMusNeuroblastomaOralPatientsPharmaceutical PreparationsPharmacologyPhasePhase I Clinical TrialsPlasmaPre-Clinical ModelPrimary NeoplasmProtocols documentationReactive Oxygen SpeciesReceptor ActivationRelative (related person)ReportingResidual NeoplasmResistanceRetinoic Acid ReceptorRetinoid ReceptorRetinoidsRoleSafingolScheduleSerineSmall Interfering RNATestingTissuesTopotecanToxic effectTransferaseTretinoinTumor BurdenTumor TissueXenograft ModelXenograft procedurebasec-Myc Staining Methodc-myc Geneschemotherapycytochrome ccytotoxiccytotoxicitydesigndosageenzyme activityhigh riskimprovedin vivoinhibitor/antagonistmitochondrial dysfunctionmitochondrial membraneneoplastic cellnoveloverexpressionpre-clinicalpreclinical studypreventreceptor functionresponseserine palmitoyltransferasesphinganinetumortumor xenograft
中文摘要
芬维甲素(4-HPR)是一种人工合成的维甲酸,对肿瘤细胞具有细胞毒作用,不依赖于P53。
对13-顺式维甲酸(13-cis-RA)耐药的神经母细胞瘤细胞系对4-HPR高度敏感,提示4-HPR
可能对逃避标准13-顺式-维甲酸治疗的肿瘤细胞具有临床活性。我们已经报告了4-hpr
神经酰胺增加(通过刺激从头合成),细胞毒性被协同增强
神经酰胺调节剂、萨芬戈(L-苏鞘氨醇)和PPMP(一种葡萄糖和酰神经酰胺合成酶的抑制剂)。
更好地了解这些新药物组合的作用机制,并评估其活性和
在动物模型中的药代动力学,将促进其临床发展。我们假设4个星球的大部分-
HPR和4-HPR safingol或PPMP依赖于4-HPR刺激CFE新生神经酰胺合成的能力。我们
将使用反义和/或siRNA来抑制丝氨酸棕榈酰转移酶(SPT),这是神经酰胺合成的限速步骤
明确神经酰胺在这些药物的细胞毒性中的作用(特定目标1)以及导致事件的分子顺序
致细胞死亡(特定目标2)。因为myc过表达(MCYN或c-myc)似乎增加了4-hpr的细胞毒性。
维甲酸可以降低MYCN的表达,在一些神经母细胞瘤细胞系中拮抗4-HPR,我们
假设高水平的myc可能促进4-HPR的细胞毒作用。在具体目标3中,我们将使用强制过度省略
以确定myc表达对4-HPR,safingol,
和PPMP。我们将确定维甲酸对4-HPR的拮抗作用是否通过维甲酸受体和/或
与MYCN表达降低有关。最后,我们假设,在适当的配方下,4-HPR
萨芬戈和/或PPMP将向组织传递肿瘤有效药物水平,并在体内具有抗神经母细胞瘤的活性
具有可耐受的全身毒性。我们将在特定目标的动物模型和临床试验中检验这一假说。
已经开发出(通过RAID和FLAIR赠款支持)适用于静脉输液的新的非肠外配方
用于治疗人类和小鼠异种移植(由I.P.注射)加4-HPR萨芬戈和/或PPMP。我们还有
开发了一种儿科口服4-HPR制剂。我们将研究这些药物的不同组合和剂量时间表
人神经母细胞瘤移植瘤对已建立肿瘤和微小残留病的抑制作用
免疫功能低下的小鼠。药理学(血浆和细胞内药物水平)将对这两个
临床前研究和我们计划的I期临床试验,使我们能够设计更好地反映
临床情况。综上所述,这里提出的研究将进一步加深我们对作用机制和
4-HPR神经酰胺调节剂在神经母细胞瘤中的体内活性,并将促进未来I、II和III期的设计
这些药物治疗神经母细胞瘤的临床试验,以及对其他儿童和成人癌症的可能治疗。
英文摘要
Fenretinide (4-HPR) is a synthetic retinoid that is cytotoxic for tumor cells in a p53-independent manner and
neuroblastoma cell lines resistant to 13-cis-retinoic acid (13-cis-RA) are highly sensitive to 4-HPR, suggesting 4-HPR
may have clinical activity against tumor cells escaping standard 13-cis-RA therapy. We have reported that 4-HPR
increased ceramides (via stimulation of de novo synthesis) and that cytoxicity was synergistically enhanced by the
ceramide modulators, safingol (L-threo-sphinganine), and PPMP (an inhibitor of glucosyl- and acylceramide synthases).
A better understanding of the mechanisms of action of these novel drug combinations, and assessing activity and
pharmacokinetics in animal models, will facilitate their clinical development. We hypothesize that a major portion of 4-
HPR and 4-HPR + safingol or PPMP is dependent on the ability of 4-HPR to stimulate cfe novo ceramide synthesis. We
will use anti-sense and/or siRNA to serine palmitoyl transferase (SPT), the rate-limiting step in ceramide synthesis, to
define the role of ceramides in cytotoxicity of these agents (Specific Aim 1) and the molecular ordering of events leading
to cell death (Specific Aim 2). Because myc overexpression (MCYN or c-myc) appears to increase cytotoxicity of 4-HPR
and retinoic acid, which can decrease MYCN expression, antagonizes 4-HPR in some neuroblastoma cell lines, we
hypothesize that high myc levels may facilitate 4-HPR cytotoxicity. In Specific Aim 3 we will use forced overepxression
of inducible MYCN or c-myc to determine the influence of myc expression on the cytotoxic response to 4-HPR, safingol,
and PPMP. We will determine if antagonism of 4-HPR by retinoic acid is mediated via retinoid receptors and/or
associated with decreased MYCN expression. Finally, we hypothesize that with appropriate formulations, 4-HPR +
safingol and/or PPMP will deliver tumor-effective drug levels to tissues and will have anti-neuroblastoma activity in vivo
with tolerable systemic toxicity. We will test this hypothesis in animal models and clinical trials in Specific Aim 4. We
have developed (via RAID and FLAIR grant support) new parenteral formulations suitable for intravenous infusion in
humans and for treating mouse xenografts (by i.p. injection) with 4-HPR + safingol and/or PPMP. We have also
developed a pediatric oral 4-HPR formulation. We will study these drugs in various combinations and dose schedules for
activity against established tumors and minimal residual disease of human neuroblastomas xenografted in
immunocompromised mice. Pharmacology (plasma and intracellular drug levels) will be carried out for both the
preclinical studies and for our planned phase I clinical trials to enable us to design preclinical models that better reflect the
clinical situation. In summary, the studies proposed here will further our understanding of the mechanism of action and
activity in vivo of 4-HPR + ceramide modulators in neuroblastoma and will facilitate the design of future phase I, II, and III
clinical trials of these druas for neuroblastoma and likelv for other childhood and adult cancers.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Targeting Shared Vulnerabilities in Alternate Telomere Lengthening (ALT) Cancers
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批准号:10390601
-
项目类别:
-
资助金额:$38.41万
-
财政年份:2022
-
负责人:CHARLES Patrick REYNOLDS
-
依托单位:
Targeting Shared Vulnerabilities in Alternate Telomere Lengthening (ALT) Cancers
-
批准号:10543855
-
项目类别:
-
资助金额:$37.64万
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财政年份:2022
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负责人:CHARLES Patrick REYNOLDS
-
依托单位:
Robust assays to define telomere maintenance mechanisms as cancer biomarkers.
-
批准号:10300210
-
项目类别:
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资助金额:$41.27万
-
财政年份:2021
-
负责人:CHARLES Patrick REYNOLDS
-
依托单位:
Robust assays to define telomere maintenance mechanisms as cancer biomarkers.
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批准号:10693944
-
项目类别:
-
资助金额:$35.83万
-
财政年份:2021
-
负责人:CHARLES Patrick REYNOLDS
-
依托单位:
Alternate telomere maintenance mechanisms in high-risk neuroblastoma as prognostic indicators and therapeutic targets
-
批准号:10225312
-
项目类别:
-
资助金额:$35.0万
-
财政年份:2018
-
负责人:CHARLES Patrick REYNOLDS
-
依托单位:
Alternate Telomere Maintenance Mechanisms in High Risk Neuroblastoma as Prognostic Indicators and Therapeutic Targets Yr 1 to 5
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批准号:10366253
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项目类别:
-
资助金额:$6.0万
-
财政年份:2018
-
负责人:CHARLES Patrick REYNOLDS
-
依托单位:
Alternate telomere maintenance mechanisms in high-risk neuroblastoma as prognostic indicators and therapeutic targets
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批准号:10472494
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项目类别:
-
资助金额:$34.3万
-
财政年份:2018
-
负责人:CHARLES Patrick REYNOLDS
-
依托单位:
A Phase I trial combining fenretinide and safingol to target overproduction of di
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批准号:8291974
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项目类别:
-
资助金额:$31.17万
-
财政年份:2011
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负责人:CHARLES Patrick REYNOLDS
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依托单位:
A Phase I trial combining fenretinide and safingol to target overproduction of di
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批准号:8188810
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项目类别:
-
资助金额:$32.37万
-
财政年份:2011
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负责人:CHARLES Patrick REYNOLDS
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依托单位:
RETINOID THERAPY
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批准号:6949341
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项目类别:
-
资助金额:$16.94万
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财政年份:2005
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负责人:CHARLES Patrick REYNOLDS
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依托单位:
Xenograft models of human neuroblastoma bone metastases.
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批准号:6687132
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项目类别:
-
资助金额:$14.88万
-
财政年份:2003
-
负责人:CHARLES Patrick REYNOLDS
-
依托单位:
Xenograft models of human neuroblastoma bone metastases.
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批准号:6800139
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项目类别:
-
资助金额:$14.88万
-
财政年份:2003
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负责人:CHARLES Patrick REYNOLDS
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依托单位:
RETINOID THERAPY OF NEUROBLASTOMA
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批准号:6038551
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项目类别:
-
资助金额:$3.51万
-
财政年份:2000
-
负责人:CHARLES Patrick REYNOLDS
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依托单位:
ENHANCING ACTIVITY OF ALKYLATING AGENTS IN NEUROBLASTOMA
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批准号:6377430
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项目类别:
-
资助金额:$23.47万
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财政年份:1999
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负责人:CHARLES Patrick REYNOLDS
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依托单位:
Enhancing Activity of Alkylating Agents in Neuroblastoma
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批准号:7166034
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项目类别:
-
资助金额:$6.23万
-
财政年份:1999
-
负责人:CHARLES Patrick REYNOLDS
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依托单位:
Enhancing Activity of Alkylating Agents in Neuroblastoma
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批准号:7371065
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项目类别:
-
资助金额:$21.07万
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财政年份:1999
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负责人:CHARLES Patrick REYNOLDS
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依托单位:
ENHANCING ACTIVITY OF ALKYLATING AGENTS IN NEUROBLASTOMA
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批准号:2898580
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项目类别:
-
资助金额:$22.13万
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财政年份:1999
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负责人:CHARLES Patrick REYNOLDS
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依托单位:
Enhancing Activity of Alkylating Agents in Neuroblastoma
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批准号:7002353
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项目类别:
-
资助金额:$24.72万
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财政年份:1999
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负责人:CHARLES Patrick REYNOLDS
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依托单位:
Enhancing Activity of Alkylating Agents in Neuroblastoma
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批准号:7546971
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项目类别:
-
资助金额:$23.11万
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财政年份:1999
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负责人:CHARLES Patrick REYNOLDS
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依托单位:
Enhancing Activity of Alkylating Agents in Neuroblastoma
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批准号:8013315
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项目类别:
-
资助金额:$22.92万
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财政年份:1999
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负责人:CHARLES Patrick REYNOLDS
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依托单位:
海外基金