Virotherapy for pancreatic cancer with wildtype and armed Myxoma viruses

使用野生型和武装粘液瘤病毒对胰腺癌进行病毒疗法

基本信息

批准号：
8044924
负责人：
Grant McFadden
金额：
$ 19.12万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8044924
关键词：
Adverse effects Animal Model Antiviral Agents Biological Response Modifier Therapy Brain Neoplasms Cancer Model Cells Chemosensitization Chemotherapy-Oncologic Procedure Clinical Deoxycytidine Kinase Engineering Equilibrative Nucleoside Transporter 1 Erlotinib Exhibits Failure Genes Glioma Grant Health Human Immunocompetent Immunodeficient Mouse In Vitro Interferon Type I Investigational New Drug Application Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Modeling Mus Myxoma virus Oncolytic Oncolytic viruses Oryctolagus cuniculus Pancreatic carcinoma Pathogenicity Pharmaceutical Preparations Poxviridae Production Publishing Recombinants Recording of previous events Refractory Regimen Reporting Resistance Rhabdoid Tumor Route Safety Signal Pathway Therapeutic Therapeutic Effect Toxic effect Transgenes Tropism Tumor Burden Tumor Necrosis Factor-alpha United States Food and Drug Administration Up-Regulation Virus Virus Diseases Virus Replication arm base cancer cell cancer therapy cell type chemotherapy clinically relevant gemcitabine improved in vivo killings medulloblastoma melanoma novel oncolysis outcome forecast pancreatic cancer cells pre-clinical recombinant virus research study response therapeutic transgene transgene expression tumor

项目摘要

DESCRIPTION (provided by applicant): The objective of this proposal is to investigate the use of MYXV as potential oncolytic virotherapy agent against pancreatic cancer in preclinical animal models. The proposal focuses on MYXV, and is based on our previously published reports and supporting preliminary studies. MYXV is a rabbit-specific poxvirus with oncolytic activity against many types of human cancer models in vivo, including brain tumors, melanoma and rhabdoid tumors. In addition, we reported recently that MYXV is able to infect and kill pancreatic cancer cells in vitro. Our preliminary studies provided in the main body of the proposal show that MYXV exhibits potent oncolytic activity in both immunodeficient and immunocompetent animal models of pancreatic cancer. Based on these results, we seek to evaluate MYXV in combination with current chemotherapy regimens, especially gemcitabine, for pancreatic cancer. We hypothesize that MYXV will have potent oncolytic activity against pancreatic cancer in vivo and may be combined and/or engineered to enhance current chemotherapy treatments. Wildtype MYXV and recombinant MYXV "armed" with chemosensitizing gene(s) will be evaluated as single agent therapies and in combination with current chemotherapy drugs approved for the treatment of pancreatic cancer. For the purposes of this grant, we propose to: 1) Evaluate the efficacy of wildtype MYXV oncolysis in murine models of pancreatic carcinoma. MYXV will be evaluated: a) as a single agent therapy compared to standard chemotherapies, b) in combination with gemcitabine and/or erlotinib, and as c) second line treatment therapy for chemotherapy resistant tumors. These experiments involve the use of the most common first line chemotherapies for pancreatic cancer and will therefore evaluate MYXV in the context of a clinically relevant scenario. Immunodeficient and immunocompetent murine models of pancreatic cancer will be established intraperitoneally (IP) and virus will be administered locally by the IP route. Tumor burden and survival curves will be compared between treatment groups in the presence or absence of gemcitabine and in gemcitabine refractory tumors to determine if MYXV virotherapy under the three regimes mentioned above results in an enhancement of therapeutic benefits as measured by tumor burden and survival. 2) Generate recombinant MYXV armed with chemosensitizing genes that will enhance gemcitabine-based chemotherapy. Recombinant "armed" MYXVs that express deoxycytidine kinase (CDK) or the human equilibrative nucleoside transporter 1(hENT-1) will be engineered. These viruses will be characterized in vivo to determine if the expression of the transgenes enhances gemcitabine-based oncolysis of pancreatic cancer cells in the two models described above in Specific Aim 1. Tumor burden and survival curves will be compared between armed and wildtype MYXVs treated groups to determine if the use of an armed MYXV provides a therapeutic advantage over wildtype MYXV by enhancing gemcitabine-based chemotherapy in vivo. This proposal will be the first study to evaluate the oncolytic potential of MYXV in preclinical animal models of pancreatic cancer as single agent therapy and in combination with chemotherapy drugs, as well as the characterization of armed MYXV capable of sensitizing cells to gemcitabine chemotherapy. Thus, if successful, these pilot experiments will identify MYXV as an effective oncolytic virus that can be further developed as a novel, safe virotherapy for the treatment of pancreatic cancer. In particular, if the results are as positive as we anticipate, and given the excellent safety profile of MYXV, we will pursue the production of clinical grade stocks of MYXV and the filing for an investigational new drug application (IND) at the completion of the proposed study.

描述（由申请人提供）：本提案的目的是研究 MYXV 作为潜在的溶瘤病毒治疗剂在临床前动物模型中对抗胰腺癌的用途。该提案重点关注 MYXV，并基于我们之前发布的报告和支持性初步研究。 MYXV 是一种兔特异性痘病毒，对体内多种人类癌症模型具有溶瘤活性，包括脑肿瘤、黑色素瘤和横纹肌样瘤。此外，我们最近报道说，MYXV能够在体外感染并杀死胰腺癌细胞。我们在提案正文中提供的初步研究表明，MYXV 在免疫缺陷和免疫功能正常的胰腺癌动物模型中均表现出强大的溶瘤活性。基于这些结果，我们寻求评估 MYXV 与当前化疗方案（尤其是吉西他滨）联合治疗胰腺癌的效果。我们假设 MYXV 在体内对胰腺癌具有有效的溶瘤活性，并且可以组合和/或改造以增强当前的化疗治疗。野生型 MYXV 和“配备”化疗敏化基因的重组 MYXV 将作为单药疗法以及与目前批准用于治疗胰腺癌的化疗药物联合进行评估。出于本次资助的目的，我们建议： 1) 评估野生型 MYXV 溶瘤作用在小鼠胰腺癌模型中的功效。 MYXV 将进行以下评估：a) 作为与标准化疗相比的单药疗法，b) 与吉西他滨和/或厄洛替尼组合，以及 c) 作为化疗耐药肿瘤的二线治疗疗法。这些实验涉及使用最常见的胰腺癌一线化疗，因此将在临床相关情况下评估 MYXV。将通过腹膜内（IP）建立免疫缺陷和免疫功能健全的小鼠胰腺癌模型，并通过IP途径局部施用病毒。将比较存在或不存在吉西他滨的治疗组和吉西他滨难治性肿瘤的治疗组之间的肿瘤负荷和生存曲线，以确定上述三种方案下的 MYXV 病毒治疗是否导致通过肿瘤负荷和生存衡量的治疗益处的增强。 2) 生成携带化疗增敏基因的重组 MYXV，该基因将增强基于吉西他滨的化疗。将设计表达脱氧胞苷激酶 (CDK) 或人类平衡核苷转运蛋白 1 (hENT-1) 的重组“武装”MYXV。这些病毒将在体内进行表征，以确定转基因的表达是否增强上述特定目标 1 中所述的两种模型中基于吉西他滨的胰腺癌细胞的溶瘤作用。将比较武装型 MYXV 治疗组和野生型 MYXV 治疗组之间的肿瘤负荷和生存曲线确定使用武装 MYXV 是否通过增强基于吉西他滨的体内化疗而提供优于野生型 MYXV 的治疗优势。该提案将是第一项评估 MYXV 在胰腺癌临床前动物模型中作为单药治疗和与化疗药物联合使用的溶瘤潜力的研究，以及表征能够使细胞对吉西他滨化疗敏感的武装 MYXV 的特征。因此，如果成功，这些试点实验将确定 MYXV 是一种有效的溶瘤病毒，可以进一步开发为治疗胰腺癌的新型、安全的病毒疗法。特别是，如果结果如我们预期的那样积极，并且考虑到 MYXV 出色的安全性，我们将继续生产 MYXV 的临床级库存，并在完成后提交研究性新药申请（IND）提议的研究。