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Virus-Targeted Therapy for Malignancies

恶性肿瘤的病毒靶向治疗

基本信息

批准号：
8124310
负责人：
SUSAN Park PERRINE
金额：
$ 28.89万
依托单位：
PHOENICIA BIOSCIENCES, INC.
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：
2011-09-26 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8124310
关键词：
Acquired Immunodeficiency Syndrome Adverse event African Burkitt&apos s lymphoma Animal Model Antiviral Agents Arginine Butyrate B-Cell Lymphomas Breast Cancer Cell Breast Carcinoma Burkitt Lymphoma Cells Central Nervous System Lymphoma Clinical Clinical Trials Cytomegalovirus Data Depsipeptides Development Disease Dose Drug Exposure Drug Kinetics Drug usage EBV-associated malignancy Enzymes Epstein-Barr Virus Infections Family Ganciclovir Gene Expression Generations Goals Herpesviridae Histone Deacetylase Histone Deacetylase Inhibitor Hodgkin Disease Hospitals Human Human Herpesvirus 4 Human Herpesvirus 6 Inpatients Intravenous infusion procedures Isoenzymes Lymphoma Lymphoproliferative Disorders MS-275 Malignant Neoplasms Malignant lymphoid neoplasm Measures Molecular Target Nasopharynx Carcinoma Neoplasms Normal Cell Nucleosides Outcome PXD101 Patients Pharmaceutical Preparations Phase Play Preparation Prevalence Publishing Radiation Regimen Reporting Resistance Role Safety Satellite Viruses Small Business Technology Transfer Research Solid Neoplasm Specificity Stomach Carcinoma TK Gene Testing Therapeutic Therapy Clinical Trials Thymidine Kinase Toxic effect Transplantation Viral Viral Drug Resistance Viral Load result Viral Proteins Virus Volatile Fatty Acids Vorinostat base cancer cell chemotherapy cytotoxicity effective therapy improved in vitro Assay killings malignant breast neoplasm malignant stomach neoplasm member mouse model neoplastic cell novel novel therapeutics novel virus nucleoside analog outcome forecast partial response research clinical testing response sarcoma therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is associated with a number of human malignancies for which there are presently few effective treatments. Lymphoid malignancies caused by, or associated with, Epstein-Barr virus include Burkitt's lymphoma, T/NK lymphomas, some T- and B-cell lymphomas, approximately half of Hodgkin's lymphomas and all post-transplant lymphoproliferative disorders (LPD). EBV(+) T and T/NK lymphomas in particular generally have an ominous prognosis, as does LPD if monoclonal. Solid tumors associated with the presence of latent EBV include nasopharyngeal carcinoma (NPC), gastric cancer, and breast cancer. The key to EBV's prevalence is its ability to persist in a dormant or "latent" state. EBV is a Herpesvirus, and many Herpes-family virus-infected cells can be killed by nucleoside analog antiviral drugs like ganciclovir, which target the viral thymidine kinase (TK) enzyme. Unlike other members of the Herpesvirus family, however, EBV is resistant to these antiviral agents, because latently-infected cells do not express the viral (TK) enzyme. We have demonstrated in in vitro assays on human tumor cells that selected agents which induce the EBV TK gene expression in these cells renders them susceptible to standard anti-viral agents. We then conducted and published a Phase I/II study to determine the tolerability/toxicity and efficacy of combined TK-inducing agent plus ganciclovir (IND #47,529) in 15 patients with EBV-associated lymphomas or LPD, all of which were completely resistant to conventional radiation and chemotherapy. Our targeted therapy produced complete clinical responses (CRs) in 4/15 patients, and good partial responses (PRs) in an additional 6 patients (total response rate of 67%). This is a truly targeted therapy, in that only the tumor cells (containing EBV) are killed -- normal cells are spared. This novel therapeutic strategy thus identified a novel target (a cancer-associated virus) present only in the tumor cells, and utilized pharmacological induction of a viral protein to make the cells susceptible to a conventional anti-viral agent. The unique features of the strategy include the molecular target and the specificity of the approach (virus-negative [normal] cells will be spared. The only major limitation of the current therapeutic regimen is that the drug used to induce the virus must be given by continuous IV infusion, in hospital, over many days. This proposal will identify and test much more active inducers of the TK gene, which can be administered on a more convenient basis, to improve this targeted therapeutic approach. We will focus specifically on short-chain fatty acid derivatives (SCFAD) or HDAC inhibitors which are approved or nearing approval, have superior pharmacokinetics, and are more selective in their actions on the EBV TK gene than our current generation drug. We will also select the optimal nucleoside anti-viral for EBV-selective tumor cytotoxicity. Selected inducers will be tested in combination with the optimal anti-viral agent in a mouse model of human EBV+ cancer. The outcome will be a more potent, selective, and more widely-accessibly therapy for EBV+ cancers and LPD. PUBLIC HEALTH RELEVANCE: Latent Epstein-Barr virus (EBV) is associated with a number of human malignancies and lymphoid proliferative diseases for which there are presently few effective treatments. We have developed a novel virus-targeted therapeutic approach, combining an agent to induce the virus out of latency together with an approved anti-viral agent, to treat these malignancies and lymphoid proliferative diseases, and have demonstrated safety and significant efficacy in a Phase I/II clinical trial. We propose here to identify a more potent and optimized inducing agent and antiviral agent, and demonstrate their anti-tumor activity in an animal model.

描述（由申请人提供）：EB病毒（EBV）与许多人类恶性肿瘤有关，目前对此几乎没有有效的治疗方法。由 Epstein-Barr 病毒引起或与之相关的淋巴恶性肿瘤包括伯基特淋巴瘤、T/NK 淋巴瘤、一些 T 细胞和 B 细胞淋巴瘤、大约一半的霍奇金淋巴瘤以及所有移植后淋巴增殖性疾病 (LPD)。 EBV(+) T 和 T/NK 淋巴瘤通常预后不良，单克隆 LPD 也是如此。与潜伏 EBV 存在相关的实体瘤包括鼻咽癌 (NPC)、胃癌和乳腺癌。 EB 病毒流行的关键在于其能够持续处于休眠或“潜伏”状态。 EBV 是一种疱疹病毒，许多疱疹家族病毒感染的细胞可以被核苷类似物抗病毒药物（如更昔洛韦）杀死，这些药物针对的是病毒胸苷激酶 (TK) 酶。然而，与疱疹病毒家族的其他成员不同的是，EBV 对这些抗病毒药物具有抵抗力，因为潜伏感染的细胞不表达病毒 (TK) 酶。我们在人类肿瘤细胞的体外测定中证明，选择诱导这些细胞中 EBV TK 基因表达的药物使它们对标准抗病毒药物敏感。然后，我们进行并发表了一项 I/II 期研究，以确定 TK 诱导剂加更昔洛韦 (IND #47,529) 组合对 15 名 EBV 相关淋巴瘤或 LPD 患者的耐受性/毒性和疗效，所有这些患者对常规放疗和化疗均完全耐药。我们的靶向治疗在 4/15 名患者中产生了完全临床缓解 (CR)，并在另外 6 名患者中产生了良好的部分缓解 (PR)（总缓解率为 67%）。这是一种真正的靶向治疗，因为只有肿瘤细胞（含有 EBV）被杀死，而正常细胞则幸免于难。因此，这种新颖的治疗策略确定了仅存在于肿瘤细胞中的新靶点（癌症相关病毒），并利用病毒蛋白的药理学诱导使细胞对常规抗病毒剂敏感。该策略的独特之处包括分子靶标和方法的特异性（病毒阴性[正常]细胞将被幸免。当前治疗方案的唯一主要限制是用于诱导病毒的药物必须在医院内通过连续静脉输注多日给予。该提案将鉴定和测试更活跃的 TK 基因诱导剂，可以更方便地施用，以改善这种靶向性治疗方法。我们将特别关注已批准或接近批准的短链脂肪酸衍生物 (SCFAD) 或 HDAC 抑制剂，它们具有优异的药代动力学，并且比我们当前一代的药物对 EBV TK 基因的作用更具选择性。我们还将针对 EBV 选择性肿瘤细胞毒性选择最佳的核苷抗病毒药物。选定的诱导剂将进行组合测试在人类 EBV+ 癌症小鼠模型中使用最佳抗病毒药物。其结果将是针对 EBV+ 癌症和 LPD 提供更有效、选择性更强、更容易获得的疗法。公共卫生相关性：潜伏性 Epstein-Barr 病毒 (EBV) 与许多人类恶性肿瘤和淋巴增殖性疾病有关，目前尚无有效的治疗方法。我们开发了一种新型病毒靶向治疗方法，将诱导病毒脱离潜伏期的药物与已批准的抗病毒药物结合起来，治疗这些恶性肿瘤和淋巴增殖性疾病，并在 I/II 期临床试验中证明了安全性和显着疗效。我们在此建议鉴定一种更有效和更优化的诱导剂和抗病毒剂，并在动物模型中证明它们的抗肿瘤活性。