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IGF1R-targeted oncolytic herpes simplex viral therapy for Glioblastoma

IGF1R-targeted oncolytic herpes simplex viral therapy for Glioblastoma
IGF1R 靶向溶瘤单纯疱疹病毒治疗胶质母细胞瘤
批准号:
10452777
负责人:
Ji Young Yoo
金额:
$20.24万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-04-01 至 2024-03-31
关键词:
Blood VesselsBrainCell ProliferationCellsChemoresistanceClinicalClinical TrialsCoupledCytometryDataDevelopmentDrug Delivery SystemsDrug resistanceGene set enrichment analysisGenerationsGenesGlioblastomaGliomaGrantGrowth Factor ReceptorsHerpes Simplex InfectionsHerpesvirus 1IGF2R geneImmuneImmunosuppressionIn VitroInjectableInsulin ReceptorInsulin-Like Growth Factor IIInsulin-Like-Growth Factor I ReceptorJapanMediatingMetastatic MelanomaModalityModelingMolecularMusNeoplasm MetastasisNeuronsOncolyticOncolytic virusesPathway interactionsPatientsPenetrationPopulationPrimary Brain NeoplasmsQuality of lifeReceptor ActivationReceptor InhibitionReceptor SignalingRecurrenceRegulatory T-LymphocyteResearchResistanceResistance developmentSafetySignal PathwaySignal TransductionSurvival RateTestingTherapeuticTherapeutic UsesTranslatingTranslationsTreatment EfficacyTumor EscapeTumor ImmunityTumor-associated macrophagesUnresectableViralVirotherapyangiogenesisanti-tumor immune responsebaseblood-brain barrier penetrationcancer cellcancer therapycancer typecell killingcell typegene therapyimprovedin vivoinnovationinsulin secretionmigrationneoplasticneoplastic cellnext generationnovelnovel therapeutic interventionnovel therapeuticsoncolytic herpes simplex virusoncolytic virotherapyoverexpressionpeptide hormonepre-clinicalreceptorsingle-cell RNA sequencingsmall molecule inhibitortherapy resistanttranscription factortranscriptome sequencingtumortumor growthtumor heterogeneitytumor microenvironmenttumor progressiontumor-immune system interactionstumorigenic

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英文摘要
PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is an aggressive and lethal form of primary brain tumor. Compared to other types of cancers which have benefited from recent therapeutic advances, little progress has been made in GBM for years. Therefore, novel therapeutic approaches are critically needed for GBM patients. The FDA recently approved an oncolytic herpes simplex virus-1 (oHSV), Talimogene Laherparepvec (IMLYGIC®), for unresectable metastatic melanoma patients. Likewise, the oHSV Delytact®, which is marketed by Daiichi Sankyo, was recently granted conditional approval in Japan for therapeutic use against GBM. However, despite this potent therapeutic modality, the therapeutic efficacy of oHSV is often diminished due to rapid viral clearance, increased angiogenesis, pro-tumorigenic signaling, and immune evasion by tumor cells and cells within the tumor microenvironment (TME), thereby becoming more resistant to therapies. Thus, it is critical to understand the precise molecular mechanisms by which tumor cells develop resistance to oHSV-mediated direct cell killing and evade oHSV-induced anti-tumor immunity for the development of more effective oHSV- based therapies for GBM patients. Our preliminary unpublished data shows that oHSV therapy increases expression and secretion of Insulin-like Growth Factor 2 (IGF2), resulting in the activation of the Insulin-like Growth Factor-1 Receptor (IGF1R) pathway in infected tumor cells. Compromising the IGF2-IGF1R signaling by the small molecule inhibitor for IGF1R, OSI-906, significantly increases oHSV-induced tumor cell killing in vitro. However, combination treatment with oHSV and OSI-906 did not show efficacy for intracranial GBM- bearing mice in vivo due to lack of brain penetration by OSI-906. Thus, we hypothesize that: (A) oHSV- triggered activation of IGF1R signaling through IGF2 expression/secretion into the TME will critically limit the therapeutic impact of oHSV, leading to enhanced tumor regrowth and immune suppression and (B) compromised IGF1R signaling utilizing a decoy receptor for IGF2 will augment oHSV therapeutic efficacy. To translate this observation into oHSV-based gene therapy, we generated a novel oHSV (oHSV-IGF2RD11Fc), which expresses IGF2R domain 11 to function as an IGF2 decoy receptor. We will test our hypotheses with the following aims: Aim 1) Identify the molecular mechanism behind oHSV-induced IGF2 expression and secretion, and evaluate the consequences of IGF1R activation in the tumor and TME; Aim 2) Characterize the mechanism of action of oHSV-IGF2RD11Fc in the tumor and TME of GBM and determine its therapeutic efficacy in vitro and in vivo. To our knowledge, this is the first study to investigate the impact of activated IGF2- IGF1R signaling on oHSV-treated tumor as well as the consequence of IGF1R blockade by oHSV- IGF2RD11Fc for GBM therapy. Data obtained from the proposed study will provide a rationale for the combination of oHSV with IGF1R blockade to accelerate the translation of oHSV therapy to an efficient and improved treatment option for GBM patients in clinical settings.
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Enhanced Viro-Immunotherapy for Breast Cancer Brain Metastasis
IGF1R-targeted oncolytic herpes simplex viral therapy for Glioblastoma
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