An Inducible Swine Hepatocellular Carcinoma Platform for Enhanced Therapeutic Development
An Inducible Swine Hepatocellular Carcinoma Platform for Enhanced Therapeutic Development
批准号:
10758109
负责人:
Derek Matthew Korpela
金额:
$34.22万
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
项目状态:
已结题
起止时间:
2023-09-01 至 2024-08-31
关键词:
AblationAccelerationAchievementAddressAnatomyAnimal ModelAnimalsAutopsyBAY 54-9085Biological MarkersBiopsyCRISPR/Cas technologyCirrhosisClinicClinicalClinical TrialsDNA Sequence AlterationDNA sequencingDataDevelopmentDevicesDiagnosisDiagnosticDiseaseDisease ManagementDrug Delivery SystemsEarly DiagnosisEnrollmentEtiologyExcisionFailureFamily suidaeFibrosisFutureGenesGeneticGenetic InductionHepaticHistopathologyHumanImageImaging technologyImmunityImmunologicsInjectionsInterventionKnock-outLifeLiverLiver diseasesLiver neoplasmsMalignant NeoplasmsMalignant neoplasm of liverMeasurementMedical DeviceMetabolismMethodsMiniature SwineModelingMolecularMolecular ProfilingMonitorNatureOncogenesOperative Surgical ProceduresOutcomePathologicPathologyPatient-Focused OutcomesPatientsPharmaceutical PreparationsPharmacologic SubstancePhasePhysiologicalPhysiologyPre-Clinical ModelPreclinical TestingPrimary Malignant Neoplasm of LiverPrimary carcinoma of the liver cellsProcessRadiation therapyRecurrenceRefractoryReproducibilityResearch PersonnelRiskRodentSafetySolidStage at DiagnosisSteatohepatitisSurvival RateSystemic TherapyTechniquesTechnologyTestingTherapeuticTherapeutic EmbolizationTimeTranslatingTransplantation SurgeryTumor BurdenTumor Suppressor GenesTumor TissueUnresectableVariantVirus DiseasesWorkadvanced diseasebeta cateninbiliary tractbiomarker identificationbiomarker validationcancer diagnosischemotherapyclinically relevantcommercializationcomorbiditycost effectiveeffective therapyglobal healthimaging modalityimprovedimproved outcomeinnovationliver cancer modelliver functionmolecular modelingmolecular phenotypemolecular subtypesmolecular targeted therapiesmortalitynoveloptimal treatmentsoverexpressionpalliativepatient populationpatient subsetspharmacokinetics and pharmacodynamicsporcine modelprecision medicinepreclinical studypreventresponsesomatic cell gene editingspecific biomarkersstandard of caresuccesstargeted treatmenttherapeutic developmenttherapeutic evaluationtherapeutically effectivetooltumortumor heterogeneitytumor microenvironmenttumorigenesistwo-arm studyultrasound
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Hepatocellular carcinoma (HCC) is a global health burden ranking as the fourth most common and second
deadliest cancer in the world. Effective therapeutic strategies for HCC, especially at advanced stages, are limited
due to tumor heterogeneity, underlying patient comorbidities, and lack of identified biomarkers for disease
management. Overall survival rates for advanced disease are just 5-14%, indicating that improved therapies are
needed. Historically, rodents have served as the predominant preclinical model, but results in these studies have
not translated to successful human application. Limitations of these and other models include variations in the
genetic and molecular mechanisms of tumorigenesis, inconsistencies in immunity and tumor microenvironments,
and marked differences in size, anatomy, and physiology. Shortcomings of these models create barriers to
identifying targetable biomarkers, developing device and imaging technologies, pharmaceutical treatments, and
techniques for biopsy and surgery, all of which are necessary to improve outcomes for HCC patients. To create
a platform whose preclinical testing will translate to innovation in these fields of HCC management, we have
developed methods to induce HCC in the liver of minipigs using somatic cell gene editing. Our minipig platform
is ideal for therapeutic development as the size, physiology, anatomy, and metabolism of minipigs are closely
related to humans. Moreover, liver function, segmental anatomy, biliary tree, and hepatic vasculature are
markedly similar to humans. To date, we have proven the feasibility of this approach in developing solid liver
tumors rapidly and reproducibly with induced molecular changes identified in HCC patients. In this proposal, we
aim to advance our HCC platform for use in precision medicine innovation by refining our HCC minipig models
to recapitulate the molecular phenotype specific to the most common subtype of human HCC. We will conduct
a drug study with the standard of care systemic therapy, sorafenib, to determine if our swine model responds
comparably to human patients. Achievement of these aims will help validate our novel minipig platform, and
segway into future studies (1) evaluating the safety and efficacy of molecularly targeted therapies, drug delivery
devices, and tumor embolization, ablation, and cryotherapeutic technologies, (2) developing novel imaging
methods, (3) studying processes of tumorigenesis, and (4) identifying biomarkers for early diagnosis and
therapeutic strategies. The minipig HCC platform will bring innovative approaches to HCC, translating results
preclinical studies to improved patient outcomes in the clinic by bolstering clinical trial success rates in a cost-
effective and time-efficient manner. In Phase II work, these models will be refined and developed in the context
of relevant co-morbidities such as underlying liver disease and validated in clinical trial-like scenarios as proof of
concept for commercialization.
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