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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要与其他类型相比，胶质母细胞瘤（GBM）是一种侵袭性且致命的原发性脑肿瘤。在受益于最新治疗进展的癌症中，GBM 方面几乎没有取得任何进展因此，FDA 最近迫切需要新的治疗方法。批准了溶瘤单纯疱疹病毒 1 (oHSV) Talimogene Laherparepvec (IMLYGIC®)，用于同样，由 Daiichi 销售的 oHSV Delytact®。 Sankyo 最近在日本获得有条件批准用于治疗 GBM。尽管有这种有效的治疗方式，但由于病毒快速传播，oHSV 的治疗效果常常会降低。清除、增加血管生成、促肿瘤信号传导以及肿瘤细胞和细胞的免疫逃避肿瘤微环境（TME）中，从而对治疗产生更强的抵抗力，因此，至关重要了解肿瘤细胞对 oHSV 介导的耐药性的精确分子机制直接杀死细胞并逃避 oHSV 诱导的抗肿瘤免疫，以开发更有效的 oHSV- 我们初步未发表的数据显示 oHSV 治疗有所增加。胰岛素样生长因子 2 (IGF2) 的表达和分泌，导致胰岛素样生长因子 2 的激活受感染肿瘤细胞中的生长因子 1 受体 (IGF1R) 通路受损。 IGF1R 小分子抑制剂 OSI-906 显着增加 oHSV 诱导的肿瘤细胞杀伤然而，oHSV 和 OSI-906 的联合治疗并未显示出对颅内 GBM- 的疗效。由于 OSI-906 缺乏脑渗透，因此我们研究了：(A) oHSV-。通过 IGF2 表达/分泌到 TME 中触发 IGF1R 信号的激活将严重限制 oHSV 的治疗作用，导致增强的肿瘤再生和免疫抑制（B）利用 IGF2 诱饵受体受损的 IGF1R 信号传导将增强 oHSV 的治疗效果。将这一观察结果转化为基于 oHSV 的基因治疗，我们生成了一种新型 oHSV (oHSV-IGF2RD11Fc)，它表达 IGF2R 结构域 11 作为 IGF2 诱饵受体，我们将用以下目标：目标 1) 确定 oHSV 诱导 IGF2 表达背后的分子机制，以及分泌，并评估 IGF1R 激活在肿瘤和 TME 中的后果；目标 2) 表征 oHSV-IGF2RD11Fc 在 GBM 肿瘤和 TME 中的作用机制及其治疗方法据我们所知，这是第一项研究激活的 IGF2- 的影响。 oHSV 治疗肿瘤上的 IGF1R 信号转导以及 oHSV 阻断 IGF1R 的结果 IGF2RD11Fc 用于 GBM 治疗从拟议研究中获得的数据将为该研究提供理论依据。 oHSV 与 IGF1R 阻断相结合，加速 oHSV 疗法转化为高效且有效的治疗方法改善临床环境中 GBM 患者的治疗选择。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
Rivera-Caraballo, Kimberly Ann;Nair, Mitra;Lee, Tae Jin;Kaur, Balveen;Yoo, Ji Young
通讯作者：
Yoo, Ji Young