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EBNA1 Inhibitor for Treatment of EBV-positive DLBCL

EBNA1 Inhibitor for Treatment of EBV-positive DLBCL
EBNA1 抑制剂用于治疗 EBV 阳性 DLBCL
批准号:
10719866
负责人:
PAUL M LIEBERMAN
金额:
$74.58万
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:
未结题
起止时间:
2023-07-07 至 2028-06-30
关键词:
Adverse eventAffectAftercareAgeAntineoplastic AgentsBiologicalBiological AvailabilityBiological MarkersBiopsyCell CommunicationCell Cycle ArrestCell MaintenanceCell ProliferationCell SurvivalCellsCessation of lifeClinicalClinical ResearchClinical TrialsDNA BindingDataDiseaseDoseDose LimitingDrug KineticsEcosystemEnrollmentEpstein-Barr Virus InfectionsEpstein-Barr Virus latencyEpstein-Barr Virus-Related LymphomaEpstein-Barr Virus-Related Malignant NeoplasmExhibitsFundingGene ExpressionGenesGrantHumanHuman Herpesvirus 4ImageImmune EvasionImmune responseImmunityImmunofluorescence ImmunologicImmunosuppressionIn VitroIndustryInfectionInferiorInfrastructureInvestigationKimmel Cancer Center at the Thomas Jefferson UniversityLeadLinkLymphoid CellLymphomaMaintenanceMalignant NeoplasmsMeasuresMedicalMetabolicMetabolic PathwayModalityModelingMusMyeloid CellsNasopharynx CarcinomaOncogenic VirusesOral AdministrationOrthologous GenePathway AnalysisPathway interactionsPatientsPatternPharmaceutical PreparationsPhasePhase I Clinical TrialsPhase II Clinical TrialsPhase Ib Clinical TrialPlasmaProcessPrognosisPropertyProteinsRNARecommendationResearch PersonnelRoleSafetySerious Adverse EventSignal PathwaySignal TransductionSpecimenStable DiseaseStromal CellsTestingThe Wistar InstituteTherapeuticTherapeutic AgentsToxic effectToxicologyUniversitiesViralViral GenesViral GenomeViral Load resultViral Oncogenecancer stem cellcarcinogenesiscell growthchemotherapyclinical candidatefirst-in-humangenetic regulatory proteinhuman studyimmune functionin vivoinhibitorlarge cell Diffuse non-Hodgkin&aposs lymphomalead optimizationmedication safetyneoplastic cellnovelnovel therapeutic interventionopen labelpatient populationpharmacologicphase 1 studypre-clinicalpreclinical studypreventresponsesmall molecule inhibitorspecific biomarkersstem cell populationstem cellstranscriptomic profilingtranscriptomicstranslational scientisttreatment effecttumortumor growthtumor microenvironmenttumor-immune system interactionstumorigenesis

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英文摘要
PROJECT SUMMARY The Epstein-Barr Virus (EBV) is responsible for approximately 200,000 new cancer cases each year worldwide. Among these, EBV+ Diffuse Large B-Cell Lymphoma (DLBCL) is an emergent global cancer threat in patients without overt immunosuppression, irrespective of age, and represents a growing unmet medical need. New therapeutic approaches are needed to treat EBV+ DLBCL. Only one viral-encoded protein, EBNA1, is consistently expressed in all known EBV-associated malignancies and is a validated target for inhibition of EBV- dependent transformation and carcinogenesis. Investigators at the Wistar Institute have developed VK-2019, a first-in-class EBNA1 inhibitor as a therapeutic agent, selecting it from over 2500 candidate inhibitor compounds during the hit-to-lead and lead optimization phases. VK-2019 meets or exceeds industry-accepted criteria for potency, selectivity, metabolic stability, drug suitability, drug safety, toxicology and bioavailability. We anticipated that VK-2019 would have a favorable safety profile because there are no human orthologs of EBNA1. Based on preclinical evidence and a first-in-human Phase I clinical study in patients with advanced nasopharyngeal carcinoma (NPC), VK-2019 met all safety, tolerability and pharmacokinetic endpoints with few documented adverse events (AEs) or Severe Adverse Events (SAEs). In this early study, we observed stable disease in more than a third and a significant decrease in EBV plasma levels, a known biomarker of NPC progression, in more than half of the patients, that correlated with pharmacokinetic exposure. We believe that data from this Phase I study are encouraging in terms of both on target effect and clinical benefit, and supports a follow-on proof-of-concept study in patients with EBV-positive DLBCL. The purpose of this grant is to fund a phase Ib clinical trial of daily oral administration of VK-2019 to (1) further confirm the safety profile and determine any dose-limiting toxicities (DLT) in advanced EBV+ DLBCL patient populations; (2) understand the effects of treatment on EBV-specific biomarkers, including EBV and cellular gene expression and (3) study the effects of treatment on the tumor microenvironment and immune response. The clinical trial infrastructure necessary for the conduct of this study is already in place at the Sidney Kimmel Cancer Center at Thomas Jefferson University. This clinical trial will provide critical information on the safety, tolerability, and preliminary efficacy of VK-2019 in a EBV+ DLBCL patient population. This application brings together basic and translational investigators to understand whether EBNA1 inhibitors can be a therapeutic option for latent EBV infection and cancer and examines the mechanism of action.
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Project 4: Regulation of EBV Latency and Oncogenesis by Hypoxia
  • 批准号:
    10714176
  • 项目类别:
  • 资助金额:
    $47.49万
  • 财政年份:
    2023
  • 负责人:
    PAUL M LIEBERMAN
  • 依托单位:
Epigenomic Drivers of EBV Epithelial Cancers
  • 批准号:
    10627690
  • 项目类别:
  • 资助金额:
    $46.97万
  • 财政年份:
    2023
  • 负责人:
    PAUL M LIEBERMAN
  • 依托单位:
Targeting the Epigenetic and Metabolic Control of EBV-Epithelial Cancers
  • 批准号:
    10627689
  • 项目类别:
  • 资助金额:
    $243.61万
  • 财政年份:
    2023
  • 负责人:
    PAUL M LIEBERMAN
  • 依托单位:
Administrative and Biostatistics
  • 批准号:
    10627693
  • 项目类别:
  • 资助金额:
    $15.99万
  • 财政年份:
    2023
  • 负责人:
    PAUL M LIEBERMAN
  • 依托单位:
海外基金