IGF1R-targeted oncolytic herpes simplex viral therapy for Glioblastoma

项目总结/摘要 胶质母细胞瘤（GBM）是一种侵袭性和致命形式的原发性脑肿瘤。相比其他类型 在受益于最近治疗进展的癌症中，GBM几乎没有进展， 年因此，GBM患者迫切需要新的治疗方法。FDA最近 批准了溶瘤性单纯疱疹病毒-1（oHSV），Laherparepvec（IMLYGIC®），用于 不可切除的转移性黑色素瘤患者。同样，由Daiichi销售的oHSV Delytact® Sankyo最近在日本获得有条件批准用于治疗GBM。然而，在这方面， 尽管有这种有效的治疗方式，但oHSV的治疗功效经常由于快速的病毒感染而降低。 清除、增加的血管生成、促肿瘤发生信号传导和肿瘤细胞和细胞的免疫逃避 在肿瘤微环境（TME）内，从而变得对治疗更有抵抗力。因此，关键是 了解肿瘤细胞对oHSV介导的耐药的精确分子机制 直接细胞杀伤和逃避oHSV诱导的抗肿瘤免疫，以开发更有效的oHSV- GBM患者的基础治疗。我们初步未发表的数据显示，oHSV治疗增加了 胰岛素样生长因子2（IGF 2）的表达和分泌，导致胰岛素样生长因子2（IGF 2）的激活。 受感染肿瘤细胞中的生长因子-1受体（IGF 1 R）途径。影响IGF 2-IGF 1 R信号传导 IGF 1 R的小分子抑制剂OSI-906显著增加了oHSV诱导的肿瘤细胞杀伤， 体外然而，oHSV和OSI-906的联合治疗未显示出对颅内GBM的疗效。 由于缺乏OSI-906的脑渗透，我们假设：（A）oHSV-1。 通过IGF 2表达/分泌进入TME的IGF 1 R信号传导的触发激活将严重限制 oHSV的治疗影响，导致增强的肿瘤再生长和免疫抑制，和（B） 利用IGF 2的诱饵受体的受损IGF 1 R信号传导将增强oHSV治疗功效。到 将这一观察转化为基于oHSV的基因治疗，我们产生了新的oHSV（oHSV-IGF 2 RD 11 Fc）， 其表达IGF 2 R结构域11以作为IGF 2诱饵受体起作用。我们将测试我们的假设与 目的1）鉴定oHSV诱导IGF 2表达的分子机制， 分泌，并评估肿瘤和TME中IGF 1 R活化的后果;目的2）表征 oHSV-IGF 2 RD 11 Fc在GBM的肿瘤和TME中的作用机制，并确定其治疗 在体外和体内的功效。据我们所知，这是第一个研究激活的IGF 2- oHSV处理的肿瘤上的IGF 1 R信号传导以及oHSV阻断IGF 1 R的结果 IGF 2 RD 11 Fc用于GBM治疗。从拟议研究中获得的数据将为 oHSV与IGF 1 R阻断剂的组合，以加速oHSV治疗转化为有效的且 改善了临床环境中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 Our preliminary unpublished data shows that oHSV therapy increases expression and secretion of Insulin-like Growth Factor 2 (IGF2), resulting in the activation of the Insulin-like Growth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.