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: 10596655
• 负责人: Ji Young Yoo
• 金额: $ 20.24万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596655
• 关键词: Acceleration; Blood Vessels; Brain; Cell Proliferation; Cells; Chemoresistance; Clinical; Clinical Trials; Combined Modality Therapy; Coupled; Cytometry; Data; Development; Drug Delivery Systems; Drug resistance; Gene set enrichment analysis; Generations; Genes; Glioblastoma; Glioma; Grant; Growth; Growth Factor Receptors; Herpes Simplex Infections; IGF2R gene; Immune; Immunosuppression; In Vitro; Injectable; Insulin Receptor; Insulin-Like Growth Factor II; Insulin-Like-Growth Factor I Receptor; Invaded; Japan; Marketing; Mediating; Metastatic Melanoma; Modality; Modeling; Molecular; Mus; Neoplasm Metastasis; Neurons; Oncolytic; Oncolytic viruses; Pathway interactions; Patients; Penetration; Population; Primary Brain Neoplasms; Quality of life; Receptor Activation; Receptor Inhibition; Receptor Signaling; Recurrent tumor; Regulatory T-Lymphocyte; Research; Resistance; Resistance development; Safety; Signal Pathway; Signal Transduction; Survival Rate; Testing; Therapeutic; Therapeutic Uses; Translating; Translations; Treatment Efficacy; Tumor Escape; Tumor Immunity; Tumor-associated macrophages; Unresectable; Viral; Virotherapy; angiogenesis; anti-tumor immune response; blood-brain barrier penetration; cancer cell; cancer therapy; cancer type; cell killing; cell type; gene therapy; improved; in vivo; innovation; insulin secretion; migration; neoplastic; neoplastic cell; next generation; novel; novel therapeutic intervention; novel therapeutics; oncolytic herpes simplex virus; oncolytic virotherapy; overexpression; peptide hormone; pre-clinical; receptor; single-cell RNA sequencing; small molecule inhibitor; therapy resistant; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor heterogeneity; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenic

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.

项目总结/文摘

项目成果

The complex relationship between integrins and oncolytic herpes Simplex Virus 1 in high-grade glioma therapeutics.

• DOI: 10.1016/j.omto.2022.05.013
• 发表时间: 2022-09-15
• 期刊: MOLECULAR THERAPY ONCOLYTICS
• 作者: Rivera-Caraballo, Kimberly Ann;Nair, Mitra;Lee, Tae Jin;Kaur, Balveen;Yoo, Ji Young
• 通讯作者: Yoo, Ji Young