IGF1R-targeted oncolytic herpes simplex viral therapy for Glioblastoma

项目摘要/摘要 胶质母细胞瘤(GBM)是一种侵袭性和致命性的原发脑肿瘤。与其他类型相比 在受益于最近治疗进展的癌症中，GBM对于 好几年了。因此，对于GBM患者来说，迫切需要新的治疗方法。美国食品和药物管理局最近 批准了一种溶瘤单纯疱疹病毒-1(OHSV)，Talimogene Laherparepvec(Imlyic®)，用于 无法切除的转移性黑色素瘤患者。同样，由Daiichi销售的OHSV Delytact® Sankyo最近在日本被有条件地批准用于治疗GBM。然而， 尽管有这种有效的治疗方式，但由于快速病毒感染，OHSV的治疗效果往往会减弱。 肿瘤细胞和细胞清除、增加血管生成、促肿瘤信号和免疫逃避 在肿瘤微环境(TME)内，因此变得对治疗更具抵抗力。因此，至关重要的是 了解肿瘤细胞对OHSV介导的耐药的确切分子机制 直接细胞杀伤和逃避OHSV诱导的抗肿瘤免疫为发展更有效的OHSV- 针对GBM患者的基础治疗。我们未发表的初步数据显示，OHSV疗法增加了 胰岛素样生长因子2(IGF2)的表达和分泌导致胰岛素样细胞激活 感染肿瘤细胞中的生长因子-1受体(IGF1R)途径。危害IGF2-IGF1R信令 IGF1R小分子抑制剂OSI-906显著增强OHSV诱导的小鼠肿瘤细胞杀伤作用 体外培养。然而，OHSV和OSI-906联合治疗并未显示出对颅内GBM的疗效。 体内荷瘤小鼠因OSI-906缺乏脑穿透作用。因此，我们假设：(A)OHSV- 通过IGF2表达/分泌到TME中而触发的IGF1R信号的激活将严重限制 OHSV的治疗作用，导致增强肿瘤再生和免疫抑制和(B) 使用IGF2诱骗受体的IGF1R信号受损将增强OHSV的治疗效果。至 将这一观察结果转化为基于OHSV的基因治疗，我们产生了一种新的OHSV(OHSV-IGF2RD11Fc)， 其表达IGF2R结构域11以起IGF2诱骗受体的作用。我们将使用 目的：1)确定OHSV诱导IGF2表达的分子机制； 分泌，并评估IGF1R激活在肿瘤和TME中的后果；目的2)表征 OHSV-IGF2RD11Fc在GBM肿瘤和TME中的作用机制及疗效观察 体外和体内疗效观察。据我们所知，这是第一次研究激活的IGF2- OHSV治疗的肿瘤中IGF1R信号转导及OHSV阻断IGF1R的后果 IGF2RD11Fc用于GBM治疗。从拟议研究中获得的数据将为 OHSV联合IGF1R阻断加速OHSV治疗向有效和 改进了临床环境中GBM患者的治疗选择。

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 Our preliminary unpublished data shows that oHSV therapy increases expression and secretion of Insulin-like Growth Factor 2 (IGF2), resulting in the activation of the Insulin-like Growth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.