Novel therapeutics development and mechanisms of therapeutic resistance in gastrointestinal stromal tumor (GIST)
胃肠道间质瘤(GIST)的新疗法开发和耐药机制
基本信息
- 批准号:10932621
- 负责人:
- 金额:$ 24.67万
- 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:2023-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:BRAF geneBehaviorBiochemicalBiological ModelsBiologyBiopsy SpecimenCRISPR interferenceCRISPR/Cas technologyCell LineChromatin Remodeling FactorCitric Acid CycleClinicalClinical TrialsClinical Trials DesignClustered Regularly Interspaced Short Palindromic RepeatsCombined Modality TherapyComplexCustomDDR1 geneDefectDependenceDevelopmentDiseaseDrug resistanceETV1 geneElectron TransportEpigenetic ProcessExhibitsGastrointestinal NeoplasmsGastrointestinal Stromal TumorsGenerationsGenesGeneticGenomic approachGoalsGrowthHumanImatinibIn VitroInter-tumoral heterogeneityInterstitial Cell of CajalInvestigationKnockout MiceKnowledgeLoxP-flanked alleleMAP Kinase GeneMaintenanceMalignant NeoplasmsMediatingMesenchymal Cell NeoplasmMesenchymal Stem CellsMitochondriaMitogen-Activated Protein KinasesModelingMolecularMutationNF1 mutationOncogenicPDGFRA genePathologicPathway interactionsPatientsPatternPharmaceutical PreparationsPhase Ib/II TrialPilot ProjectsPopulationPre-Clinical ModelProteinsRNA InterferenceReceptor Protein-Tyrosine KinasesRegulationResistanceResistance developmentResourcesRoleSamplingSignal InductionSignal PathwaySignal TransductionSoft tissue sarcomaSpecific qualifier valueSuccinate DehydrogenaseTechnologyTherapeuticTumor Cell LineTumor SubtypeTyrosine Kinase Inhibitorcancer genomicsconditional knockoutdesigndriver mutationepigenomeepigenomicsexome sequencinggenetic approachin vitro Modelin vivoin vivo Modelinhibitorinterdisciplinary approachloss of functionmouse modelmultidisciplinarymutantnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticspre-clinicalprecursor cellresistance mechanismresponsesarcomatargeted sequencingtherapeutic developmenttherapeutic evaluationtherapeutic targettherapy resistanttumortumor initiationtumorigenesisubiquitin-protein ligase
项目摘要
RP-1: Novel Therapeutics Development and Mechanisms of Therapeutic Resistance in GIST
ABSTRACT
Gastrointestinal stromal tumor (GIST) represents one of the most prevalent sarcoma subtypes and is
the most common mesenchymal neoplasm of the GI tract. Most GISTs harbor activating oncogenic
“driver” mutations in receptor tyrosine kinases, e.g. KIT or PDGFRA. Among KIT/PDGFRA wild-type
GISTs, the majority harbor loss-of-function defects in the mitochondrial succinate dehydrogenase
(SDH) complex, a component of the Krebs cycle. KIT/PDGFRA-mutant and SDH-deficient GISTs
represent molecularly distinct groups, with distinct clinical behaviors. We have recently identified
ETV1 as a master regulator for the lineage specification and normal development of the GIST precursor
cells, the interstitial cells of Cajal. Importantly, ETV1 is required for the growth and survival of
imatinib-sensitive and -resistant GISTs in vitro and for tumor initiation and maintenance in vivo. We
hypothesize ETV1 is a novel therapeutic target that is critical for the shared lineage-dependent survival
of both imatinib-sensitive and -resistant GISTs. In this project, we propose a comprehensive study to
understand the regulation of ETV1 protein stability, and to develop novel therapeutic strategies
targeting ETV1 protein stability using various pre-clinical GIST models. In parallel, we will investigate
clinical samples from prior and ongoing clinical trials designed to target ETV1 protein stability to better
understand the molecular mechanisms of therapeutic resistance. Moreover, targeted sequencing using
custom IMPACT panels will be used on these matched pre- and post-therapy biopsy samples from the
on-going phase Ib/II trials using imatinib in combination with MEK162 to elucidate mechanism of
drug resistance. This investigation will leverage comprehensive and multidisciplinary approaches,
including biochemical, state-of-the-art genomics, and genetic approaches in in vitro and in vivo models
as well as patient tumor samples derived from current GIST clinical trials. The therapeutic strategies
identified here may benefit other ETV1-dependent malignancies. Lastly, since there are no in vitro and
in vivo models for focused mechanistic and therapeutic investigation of SDH-deficient GISTs, we will
generate cell line models through novel gene editing technology, such as CRISPR and CRISPRi, in
established GIST cell lines as well as in human mesenchymal progenitor cells that are committed to the
interstitial cells of Cajal lineage. We will also develop in vivo murine models of SDH-deficient GISTs for
focused evaluation of therapeutics specifically targeting SDH deficiency that may benefit other SDH-
deficient malignancies beyond GIST.
RP-1: GIST治疗耐药的新疗法发展和机制
项目成果
期刊论文数量(0)
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CRISTINA R ANTONESCU其他文献
CRISTINA R ANTONESCU的其他文献
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{{ truncateString('CRISTINA R ANTONESCU', 18)}}的其他基金
Novel therapeutics development and mechanisms of therapeutic resistance in gastrointestinal stromal tumor (GIST)
胃肠道间质瘤(GIST)的新疗法开发和耐药机制
- 批准号:
10468962 - 财政年份:2018
- 资助金额:
$ 24.67万 - 项目类别:
Novel therapeutics development and mechanisms of therapeutic resistance in gastrointestinal stromal tumor (GIST)
胃肠道间质瘤(GIST)的新疗法开发和耐药机制
- 批准号:
10016095 - 财政年份:2018
- 资助金额:
$ 24.67万 - 项目类别:
Novel therapeutics development and mechanisms of therapeutic resistance in gastrointestinal stromal tumor (GIST)
胃肠道间质瘤(GIST)的新疗法开发和耐药机制
- 批准号:
10247696 - 财政年份:2018
- 资助金额:
$ 24.67万 - 项目类别:
P1 - Molecular Mechanisms of KIT Signaling and Imatinib Resistance in GIST
P1 - GIST 中 KIT 信号传导和伊马替尼耐药的分子机制
- 批准号:
7976097 - 财政年份:2010
- 资助金额:
$ 24.67万 - 项目类别:
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