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

增强 Ras 靶向溶瘤单纯疱疹病毒的新策略

• 批准号: 9033087
• 负责人: SHAUN XIAOLIU ZHANG
• 金额: $ 34.93万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033087
• 关键词: Affinity; Arginine; Benign; Binding; Blood; Blood Circulation; CD47 gene; Clinical; Clinical Data; Clinical Trials; Data; Development; Disease; Eating; Endothelial Cells; Equilibrium; FRAP1 gene; Foundations; Frequencies; Glycoproteins; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Herpesvirus 1; Human Herpesvirus 2; Integrin alphaVbeta3; Integrins; Knowledge; Learning; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Minority; Modality; Modeling; Mutation; Neoplasms in Vascular Tissue; Normal tissue morphology; Oncolytic; Oncolytic viruses; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Primary Neoplasm; Property; Ras Signaling Pathway; Resistance; Reticuloendothelial System; Route; Series; Signal Transduction; Simplexvirus; Sirolimus; Solid Neoplasm; Staging; Surface; Testing; Therapeutic; Translating; Translations; Treatment Efficacy; Tumor Tissue; Variant; Viral; Virotherapy; Virus; Virus Replication; Work; alternative treatment; arginase; arm; base; cancer cell; cell killing; clinical application; deprivation; design; echistatin; improved; in vitro testing; in vivo; killings; neoplastic cell; neovasculature; novel strategies; oncolytic virotherapy; outcome forecast; overexpression; pancreatic cancer cells; particle; permissiveness; research study; response; small molecule; standard care; success; targeted delivery; tumor; tumor microenvironment

 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.

 描述（由申请人提供）：尽管最近进行了标准护理，但患有许多恶性病变（例如胰腺癌）的患者预后仍然较差，溶瘤病毒疗法是一种有前途的替代疗法，可以通过转变自然癌症病毒疗法功能为这些患者提供治疗益处。良性病毒选择性杀死癌细胞的细胞杀伤能力近年来在开发这种治疗方式方面取得了重大进展。与单独使用 GM-CSF 治疗相比，基于 HSV-1 的溶瘤病毒 T-VEC 的总生存期延长了 4.4 个月（p=0.051），虽然这些临床数据显然令人鼓舞，但它们也表明当前的癌症。病毒疗法在最终获得 FDA 批准之前还需要进一步改进，我们开发了一种基于 HSV-2 的溶瘤病毒，这是第一种被指定为 FusOn-H2 的病毒，它可以在带有 DNA 的肿瘤细胞中选择性复制。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，包括具有高频率（超过90％）Ras突变的胰腺癌。在病毒治疗的几个关键步骤中增强 FusOn-H2 的策略，包括增强递送、降低治疗耐药性和适应肿瘤微环境，主要使用胰腺癌作为肿瘤模型。我们的工作假设是：1）武装。具有“别吃我”信号的 FusOn-H2 将使病毒持续存在于血液中，并掺入与肿瘤新生血管内皮细胞上的 avß3 整合素具有强结合亲和力的 echistatin， 进入病毒将使其能够通过全身途径主动递送至肿瘤组织。 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 小分子药物的耐受性。将探索操纵这些相互作用以增加胰腺癌细胞对 FusOn-H2 病毒疗法的耐受性 3) 经常检测到的缺乏精氨酸的肿瘤微环境。在许多肿瘤中，由精氨酸酶过度表达引起，是溶瘤 HSV 病毒治疗的障碍，因为早期研究表明精氨酸酶可以有效抑制 HSV 复制，使 FusOn-H2 适应精氨酸剥夺可以克服这一障碍。该提案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。我们建议将FusOn-H2纳入的新策略有望显着提高这种病毒疗法的整体治疗效果，从而增加其治疗的可能性。 此外，其中许多策略可能适用于其他溶瘤病毒用于其他肿瘤治疗，从而使整个癌症病毒治疗领域受益。