Novel Strategies to Potentiate a Ras-targeted Oncolytic Herpes Simplex Virus

 描述(申请人提供)：尽管最近在标准护理方面有所改进，但患有许多恶性病变的患者，如胰腺癌，预后仍然很差。溶瘤病毒疗法是一种很有前途的替代治疗方法，可以为这些患者提供治疗上的好处。癌症病毒疗法的功能是将良性病毒的自然细胞杀伤能力转化为选择性地杀死癌细胞。近年来，在开发这种治疗方式方面取得了重大进展。使用基于单纯疱疹病毒1型溶瘤病毒的第三阶段临床试验的最新数据显示，与单用GM-CSF治疗相比，总生存期增加了4.4月(p=0.051)。虽然这些临床数据显然令人鼓舞，但它们也表明，目前的癌症病毒疗法需要进一步改进，才可能最终获得FDA的批准。我们已经开发出一种基于HSV-2的溶瘤病毒，这是此类病毒中的第一种。它被命名为Fuson-H2，可以选择性地在具有激活的RAS信号通路的肿瘤细胞中复制。当在体内进行评估时，它可以有效地缩小甚至根除许多恶性肿瘤，包括携带高频率(90%以上)RAS突变的胰腺癌。在这个提案中，我们将探索一系列新的策略来增强Fuson-H2在病毒治疗的几个关键步骤中的作用，包括增强递送，减少治疗阻力和适应肿瘤微环境，主要是使用胰腺癌作为肿瘤模型。我们的工作假说是：1)给Fuson-H2配备“不要吃我”的信号将允许病毒在血液中持续存在，并将与av？3整合素具有很强结合亲和力的ecichatin掺入肿瘤新生血管内皮细胞， 进入病毒将使其能够通过全身途径主动传递到肿瘤组织。2)Ras-ERK和PI3K-Akt-mTor通路之间的动态相互作用决定了胰腺癌细胞对Fuson-H2的通透性。将探索小分子药物来操纵这些相互作用，以增加胰腺癌细胞对Fuson-H2病毒治疗的通透性。3)精氨酸缺失的肿瘤微环境是由精氨酸酶过度表达引起的肿瘤微环境，是溶瘤HSV病毒治疗的障碍，因为早期研究表明精氨酸酶能有效地抑制HSV的复制。使Fuson-H2适应精氨酸缺乏可以克服这一障碍。我们设计了三个具体目标来检验这些主要假设。这项提议的最终目标是将这种基于HSV-2的溶瘤病毒转化为临床应用，主要用于治疗胰腺癌--一种预后极差的恶性疾病。我们建议纳入Fuson-H2的新策略有望显著提高这种病毒疗法的整体疗效，从而增加其 临床上的成功。此外，这些策略中的许多可能适用于用于其他肿瘤治疗的其他溶瘤病毒，从而使整个癌症病毒治疗领域受益。

 DESCRIPTION (provided by applicant): Despite recent improvements in standard care, patients with many malignant lesions such as pancreatic cancer still have poor prognoses. Oncolytic virotherapy is a promising alternative treatment that may provide therapeutic benefit to these patients. Cancer virotherapy functions by converting the natural cell killing ability of a benign virus to selectively kill cancer cells. Significant progress has been made in recent years in developing this therapeutic modality. Recent data from a phase III clinical trial using an HSV-1-based oncolytic virus, T-VEC, show an increase of 4.4 months in overall survival when compared with GM-CSF treatment alone (p=0.051). While these clinical data are clearly encouraging, they also indicate that the current cancer virotherapy needs further improvement before it may eventually gain the FDA approval. We have developed an HSV-2-based oncolytic virus, the first of this kind. Designated FusOn-H2, it can selectively replicate in tumor cells bearing an activated Ras signaling pathway. When evaluated in vivo, it can effectively shrink or even eradicate many malignant tumors, including pancreatic cancer, which harbors a high frequency (over 90%) of Ras mutation. In this proposal, we will explore a series of novel strategies to potentiate FusOn-H2 in several key steps of virotherapy, including enhancing delivery, reducing therapy resistance and adaptation to tumor microenvironment, primarily using pancreatic cancer as a tumor model. Our working hypotheses are: 1) Arming FusOn-H2 with a "don't eat me" signal will allow the virus to persist in the blood, and incorporation of echistatin which has a strong binding affinity to avß3 integrin on endothelial cells of tumor neovasculature, into the virus will enable it to be actively delivered to tumor tissues by the systemic route. 2) Te dynamic interactions between the Ras-ERK and PI3K-Akt-mTOR pathways dictate the permissiveness of pancreatic cancer cells to FusOn-H2. Small molecule drugs will be explored to manipulate these interactions to increase the permissiveness of pancreatic cancer cells to FusOn-H2 virotherapy. 3) The arginine-deprived tumor microenvironment, frequently detected in many tumors and caused by overexpression of arginase, presents as an obstacle for oncolytic HSV virotherapy, as early studies have shown that arginase can efficiently inhibit HSV replication. Adapting FusOn-H2 to arginine-deprivation can overcome this obstacle. We have designed three specific aims to test these major hypotheses. The ultimate goal of this proposal is to translate this HSV-2- based oncolytic virus into clinical application, primarily for the treatment of pancreatic cancer - a malignant disease that has an extremely poor prognosis. The novel strategies that we propose to incorporate into FusOn- H2 are expected to significantly enhance the overall therapeutic efficacy of this virotherapy, thus increasing the likelihood of its clinical success. Moreover, many of these strategies may be applicable to other oncolytic viruses for other tumor treatment, thus benefiting the entire field of cancer virotherapy.