Improving Therapeutic Approaches for RAS-driven Embryonal Rhabdomyosarcoma
改善 RAS 驱动的胚胎性横纹肌肉瘤的治疗方法
基本信息
- 批准号:10446046
- 负责人:
- 金额:$ 35.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:ApoptosisBiological AssayCell Cycle ArrestCell LineChemotherapy and/or radiationChemotherapy-Oncologic ProcedureChildClassificationClinicalClinical ProtocolsClinical TrialsClinical Trials DesignClonal EvolutionCodon NucleotidesCombined Modality TherapyDNA DamageDNA RepairDNA sequencingDataDiagnosisDiseaseDoseDown-RegulationEmbryonal RhabdomyosarcomaEventExperimental DesignsFRAP1 geneGenerationsGeneticGenomicsGoalsImmunohistochemistryInterventionLesionLifeMAP Kinase GeneMAPK Signaling Pathway PathwayMEK inhibitionMEKsMitogen-Activated Protein Kinase InhibitorModelingMusMutationNF1 geneOncogenicOperative Surgical ProceduresOutcomePathway interactionsPatientsPharmacodynamicsPilot ProjectsProtein IsoformsProto-Oncogene Proteins c-aktProtocols documentationRadiation therapyRecurrenceRegimenRegulationResistanceRhabdomyosarcomaRiskRoleScheduleSignal TransductionTestingTherapeuticToxic effectTranslationsVincristineXenograft ModelXenograft procedurebasechemoradiationchemotherapeutic agentchemotherapyepigenomicsgenetic manipulationgenotoxicityhigh riskimprovedimproved outcomein vivoin vivo Modelinhibitorinnovationknock-downmutantnovelpatient derived xenograft modelpre-clinicalpreclinical evaluationprotocol developmentresearch clinical testingresistance mechanismresponseresponse biomarkersarcomascreeningtargeted treatmenttranscriptome sequencingtreatment responsetumortumor xenograft
项目摘要
Summary
Despite the use of aggressive chemo-radiation therapy, children with high-risk rhabdomyosarcoma (RMS)
including advanced or metastatic embryonal RMS (ERMS) with RAS mutations, have very poor outcomes (20-
30% survival at 5 years from diagnosis) with no significant improvement over the last 30 years. Further, current
multimodality therapies are associated with life-long life-threatening sequelae. This project focuses on
developing less-genotoxic, targeted therapy for RAS-mutant ERMS. Preliminary data support rapid translation
of vertical targeting of the MAPK pathway as a therapeutic approach in ERMS. The proposed aims are based
upon the following observations: (i) In RAS-driven ERMS, resistance to MEK inhibitors is a consequence of
pathway reactivation through CRAF; (ii) Combination of new generation type 2 RAF inhibitors with MEK inhibitors
cause dramatic regressions of most RAS-mutant ERMS PDX models but are not curative. Consequently, both
intrinsic and acquired resistance will be a barrier for long-term curative outcomes; (iii) Innovative single mouse
testing (SMT) experimental design shows that, consistent with their high-risk classification, RAS-mutant ERMS
PDX/CDX models, rapidly fail intensive multidrug regimens used in the most recent high-risk RMS clinical
protocol (ARST0431). Therefore, this project aims to: 1) define mechanisms of innate and acquired resistance
to co-targeting RAF and MEK in RAS-driven ERMS with the goal to facilitate more impactful clinical outcomes.
Using DNA and RNA sequencing, we will identify genomic/epigenomic changes associated with resistance and
validate and define mechanisms of innate and acquired resistance to combining type 2 RAF and MEK inhibitors
in ERMS; 2) evaluate how this approach can be integrated into current clinical chemotherapy protocols using
the SMT experimental design. Our studies will inform biomarkers of response to type 2 RAF + MEK inhibitors
combination and how this combination can be sequenced relative to chemotherapy to optimize responses of
RMS PDX/CDX models, thus directly impacting clinical trials design for RAS-driven ERMS.
总结
项目成果
期刊论文数量(0)
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Angelina V Vaseva其他文献
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{{ truncateString('Angelina V Vaseva', 18)}}的其他基金
Improving Therapeutic Approaches for RAS-driven Embryonal Rhabdomyosarcoma
改善 RAS 驱动的胚胎性横纹肌肉瘤的治疗方法
- 批准号:
10563200 - 财政年份:2022
- 资助金额:
$ 35.46万 - 项目类别:
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