FEN1-Nuclease-Targeted Therapy for Ewing Sarcoma
FEN1-核酸酶靶向治疗尤文肉瘤
基本信息
- 批准号:10600872
- 负责人:
- 金额:$ 59.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAdolescentAffectAnimalsBRCA1 geneBar CodesBiological AssayBiological AvailabilityBiopsyBone TissueBone neoplasmsCRISPR libraryCRISPR/Cas technologyCell DeathCell LineCellsCessation of lifeChildChromosome BreakageClinicClustered Regularly Interspaced Short Palindromic RepeatsCollectionCoupledDNADNA Binding DomainDNA DamageDNA RepairDNA biosynthesisDependenceDrug KineticsDrug resistanceEWS-FLI1 fusion proteinEWSR1 geneEnzymesEwings sarcomaFLI1 geneFamilyFutureGenesGeneticGenetic TranscriptionGoalsGrowthGuide RNAHumanIn VitroInstitutional Review BoardsKnock-outLegal patentLettersLibrariesMalignant Childhood NeoplasmMalignant NeoplasmsMeasuresMitoticMolecularMolecular MedicineMusNude MiceOkazaki fragmentsOncoproteinsOperative Surgical ProceduresPatientsPediatric OncologistPediatricsPharmaceutical PreparationsPharmacotherapyPhenotypePrimitive Neuroectodermal TumorPrincipal InvestigatorProcessProtocols documentationRadiationReportingResearchResearch Project GrantsResectedResistanceSamplingSignal TransductionSmall Interfering RNASpecificityStatistical MethodsSurvival RateTestingTherapeuticTransactivationTransplantationTumor Cell LineTumor VolumeXenograft procedureadvanced diseaseaggressive therapybrca genecancer cellcell transformationchemotherapycytotoxicdata miningendonucleasegenome-wideimprovedin vivoin vivo evaluationinhibitormouse modelneoplastic cellnovelnovel therapeuticsnucleasepatient derived xenograft modelpatient prognosispreclinical evaluationpreclinical studyresponsesmall moleculesoft tissuesynergismtargeted nucleasestargeted treatmentthree dimensional cell culturetumortumor growthtumorigenesisyoung adult
项目摘要
PROJECT SUMMARY
Ewing Sarcoma Family of Tumors (ESFT) are bone and soft tissue cancers that affect children and adolescents.
Surgery, radiation and multi-agent chemotherapy have improved patient prognosis but a therapeutic plateau has
been reached for both localized and metastatic cases. Hence, there is an urgent need for novel and targeted
therapeutic strategies. Towards that goal, this Multi-PI collaborative research project will investigate the
hypothesis that ESFT cells are dependent on FEN1, an endonuclease that processes the 5’ flaps of Okazaki
fragments during lagging strand DNA synthesis, for viability. This hypothesis is supported by: (a) Four genome-
scale CRISPR library screens have independently found that ESFT cell lines are highly sensitive to FEN1-
CRISPRs; (b) ESFT cells were reported to be phenotypically BRCA1-deficient, and we have shown that
BRCA1/2-deficient cells are hypersensitive to FEN1 inhibition; and (c) we have found several ESFT cell lines to
be sensitive to FEN1-CRISPRs, FEN1-siRNAs and two small molecular FEN1-inhibitors. A team of three
principal investigators will jointly direct this project: RD Kolodner is a geneticist and an inventor of FEN1-inhibitors
in documented patent applications, JYJ Wang is a cancer biologist with expertise in DNA damage response, and
SH Choo is a pediatric oncologist with an ongoing IRB to conduct research with ESFT patient samples. Together,
we will pursue four specific aims to investigate the ESFT-dependency on FEN1. AIM-1: To demonstrate and to
quantify FEN1-essentiality in a panel of 10 ESFT cell lines by genetic ablation of FEN1 with validated siRNAs
and CRISPR/CAS9, respectively. AIM-2: To determine the cytotoxic effects of small molecule FEN1 inhibitors
on 10 ESFT cell lines by short-term growth and death assays and longer-term colony formation assays in 2D
and 3D cultures. We will edit FEN1 in ESFT cells to express a drug-resistant FEN1R enzyme so as to
demonstrate on-target effects. We will evaluate the potential synergistic interactions between FEN1-inhibitors
and the chemotherapeutic drugs currently used in the clinic to treat ESFT patients. AIM-3: To investigate the
mechanisms underlying ESFT dependency on FEN1 by addressing three mechanistic questions on whether (a)
the EWS-FLI1 oncoprotein of ESFT induces FEN1-dependency, (b) FEN1-inhibitors cause irreversible blockade
of DNA replication in ESFT cells, and (c) FEN1-inhibitors cause DNA breakage and mitotic catastrophe in ESFT
cells. AIM-4: To determine the effects of FEN1 inhibitors on ESFT growth in mice. We have found that a FEN1-
inhibitor (SMD154) reduced the growth of orthotopic xenografts from an ESFT cell line in athymic nude mice.
The pharmacokinetics (PK) of SMD154 support its testing on orthotopic xenografts from two ESFT cell lines that
show sufficiently low in vitro IC50 for this compound. We will construct 4-6 ESFT patient-derived xenografts (PDX)
from biopsies and resected tumors. We will test SMD154 and future FEN1-inhibitors with optimized PKs on cell
line- and patient-derived xenografts. This comprehensive preclinical study will produce a detailed understanding
of the ESFT-dependency on FEN1 and pave the way towards developing FEN1-inhibitors to treat ESFT.
项目总结
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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Sun Ha Choo其他文献
Sun Ha Choo的其他文献
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{{ truncateString('Sun Ha Choo', 18)}}的其他基金
FEN1-Nuclease-Targeted Therapy for Ewing Sarcoma
FEN1-核酸酶靶向治疗尤文肉瘤
- 批准号:
10209659 - 财政年份:2021
- 资助金额:
$ 59.16万 - 项目类别:
FEN1-Nuclease-Targeted Therapy for Ewing Sarcoma
FEN1-核酸酶靶向治疗尤文肉瘤
- 批准号:
10368155 - 财政年份:2021
- 资助金额:
$ 59.16万 - 项目类别:
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