Pilot Project Investigating the PAX3-FOXO1 Protein in the Rare Disease Rhabdomyosarcoma
研究罕见疾病横纹肌肉瘤中 PAX3-FOXO1 蛋白的试点项目
基本信息
- 批准号:10727279
- 负责人:
- 金额:$ 14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinityAlveolar RhabdomyosarcomaAntibodiesBindingBiological AssayBiological ModelsBrainCardiac MyocytesCell CompartmentationCell Culture SystemCell Cycle KineticsCell modelCellsChemicalsChemotherapy and/or radiationChildhoodChimeric ProteinsChromatinClinicalCollaborationsCommunitiesComplexComputer softwareDNA Binding DomainDataDiseaseDoseDropsEmbryonal RhabdomyosarcomaEpigenetic ProcessFOXO1A geneFibroblastsFractionationFutureFuture GenerationsGene FusionGenerationsGenetic TranscriptionGoalsIndividualJointsKnowledgeMachine LearningMalignant Childhood NeoplasmMalignant NeoplasmsMediatingModelingMolecularMuscleMyoblastsNF-kappa BNeuronsNuclearOutcomePAX3 genePAX7 genePatientsPeptidesPilot ProjectsProtein IsoformsProteinsPublishingRare DiseasesRecombinantsRecurrenceReporterResistanceResponse ElementsRhabdomyosarcomaRoleSkeletal MuscleSpecificityStructureSurface Plasmon ResonanceTestingTherapeuticTimeTransactivationTreatment FailureUniversitiesValidationcardiogenesischemical synthesischemotherapycounterscreendesignexperimental studyfusion genehomeodomainimmunogenicin silicoin vivomalignant muscle neoplasmmembermutantprotein degradationprotein expressionprotein functionscreeningsmall moleculesmall molecule inhibitorsmall molecule librariessoft tissuetherapy resistanttooltranscription factorubiquitin-protein ligasevalidation studies
项目摘要
SUMMARY
The rare childhood muscle cancer alveolar rhabdomyosarcoma (ARMS) is generally not survivable when
metastatic. However, ARMS does usually respond clinically to chemotherapy initially. With respect to the cause
of recurrences, clinicians observe that the translocation-mediated PAX3:FOXO1 chimeric protein present in most
ARMS cases mediates treatment resistance, causing a 45% drop in 10-year survival – a clinical outcome not
associated with the less common PAX7:FOXO1 protein. PAX3, PAX7 and FOXO1 are all individually key
transcription factor proteins in normal muscle, brain and heart development – yet incompletely studied. The
PAX3/7:FOXO1 fusion proteins are even less well characterized. We hypothesize that selective small
molecule inhibitors of these chimeric transcription factor can be designed as probes to uncover these
proteins' molecular, epigenetic, cellular and in vivo functions. Thus, our aim is to: (1) Develop small
molecule inhibitors of PAX3-FOXO1 and PAX7:FOXO1 as tool compounds. Our approach is to establish
PAX homeodomain and paired domain transcriptional reporter assays in a variety of cell model systems with
different epigenetic contexts (skeletal muscle myoblasts, cardiomyocytes, RMS, control fibroblasts and neuronal
cells); counter-screen for an unrelated transcriptional response element target (e.g., NFkB); perform surface
plasmon resonance affinity testing of compound hits with recombinant wildtype and mutant PAX3:FOXO1 or
PAX7:FOXO1 proteins; and perform ARMS cell compartment fractionation to define PROTAC-compatible
nuclear E3 ligases towards generation of a PROTAC tool for PAX3/7-FOXO1. From these studies, we hope to
facilitate the study of PAX3/7:FOXO1 function as transcription factors without necessarily disturbing complexes
(via small molecule inhibitors), and to allow study of epigenetic protein function in real time without secondary
effects (via eventual PROTAC tools).
总结
罕见的儿童肌肉癌腺泡状横纹肌肉瘤(ARMS)通常无法生存,
转移性的然而,ARMS通常在临床上对化疗有反应。关于我们的事业
临床医生观察到,在大多数复发性乳腺癌中,易位介导的PAX 3:FOXO 1嵌合蛋白存在于
ARMS病例介导治疗抵抗,导致10年生存率下降45%-临床结果不
与不太常见的PAX 7:FOXO 1蛋白相关。PAX 3、PAX 7和FOXO 1都是单独的关键
转录因子蛋白在正常肌肉,大脑和心脏发育中的作用-但尚未完全研究。的
PAX 3/7:FOXO 1融合蛋白的特征甚至更少。我们假设选择性的小
这些嵌合转录因子的分子抑制剂可以被设计为探针,
蛋白质的分子、表观遗传、细胞和体内功能。因此,我们的目标是:(1)发展小
作为工具化合物的PAX 3-FOXO 1和PAX 7:FOXO 1分子抑制剂。我们的方法是建立
PAX同源结构域和配对结构域转录报告基因在多种细胞模型系统中的测定,
不同的表观遗传背景(骨骼肌成肌细胞、心肌细胞、RMS、对照成纤维细胞和神经元细胞)
细胞);反筛选不相关的转录应答元件靶(例如,预制表面
用重组野生型和突变型PAX 3:FOXO 1或PAX 3:FOXO 2进行的化合物命中的等离子体共振亲和力测试
PAX 7:FOXO 1蛋白;并进行ARMS细胞室分级分离,以确定PROTAC相容性
细胞核E3连接酶的基因,以产生PAX 3/7-FOXO 1的PROTAC工具。通过这些研究,我们希望
促进PAX 3/7:FOXO 1作为转录因子功能的研究,而不一定干扰复合物
(via小分子抑制剂),并允许在真实的时间内研究表观遗传蛋白质功能,而无需二次
效果(通过最终的PROTAC工具)。
项目成果
期刊论文数量(0)
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CHARLES KELLER的其他文献
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{{ truncateString('CHARLES KELLER', 18)}}的其他基金
Clinical & Mechanistic underpinnings to reducing PAX:FOXO1 for alveolar rhabdomyosarcoma
临床
- 批准号:
10405632 - 财政年份:2021
- 资助金额:
$ 14万 - 项目类别:
Clinical & Mechanistic underpinnings to reducing PAX:FOXO1 for alveolar rhabdomyosarcoma
临床
- 批准号:
10182958 - 财政年份:2021
- 资助金额:
$ 14万 - 项目类别:
Clinical & Mechanistic underpinnings to reducing PAX:FOXO1 for alveolar rhabdomyosarcoma
临床
- 批准号:
10610429 - 财政年份:2021
- 资助金额:
$ 14万 - 项目类别:
Cytokine- and Satellite Cell-mediated Muscle Disease Promotion
细胞因子和卫星细胞介导的肌肉疾病促进
- 批准号:
9319227 - 财政年份:2015
- 资助金额:
$ 14万 - 项目类别:
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