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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相关，目前对其缺乏有效治疗。由EB病毒引起或与EB病毒相关的类淋巴瘤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和所有移植后淋巴组织增生性疾病（LPD）。特别是EBV（+）T和T/NK淋巴瘤通常预后不良，如果是单克隆的，LPD也是如此。与潜伏性EBV的存在相关的实体瘤包括鼻咽癌（NPC）、胃癌和乳腺癌。EB病毒流行的关键是它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，这些药物靶向病毒胸苷激酶（TK）酶。然而，与疱疹病毒家族的其他成员不同，EBV对这些抗病毒剂具有抗性，因为潜伏感染的细胞不表达病毒（TK）酶。我们已经在人类肿瘤细胞的体外试验中证明，选择的诱导这些细胞中EB病毒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，以确定联合TK诱导剂加更昔洛韦（IND #47，529）在15例EBV相关淋巴瘤或LPD患者中的耐受性/毒性和疗效，所有患者均对常规放疗和化疗完全耐药。我们的靶向治疗在4/15例患者中产生了完全临床应答（CR），在另外6例患者中产生了良好的部分应答（PR）（总应答率为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-正常细胞幸免。因此，这种新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点和方法的特异性（病毒阴性[正常]细胞将被保留。目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连续静脉输注许多天。该提案将鉴定和测试TK基因的更活跃的诱导剂，其可以在更方便的基础上施用，以改进这种靶向治疗方法。我们将特别关注已批准或即将批准的短链脂肪酸衍生物（SCFAD）或HDAC抑制剂，这些药物具有上级药代动力学，并且比我们当前一代药物对EBV TK基因的作用更具选择性。我们还将选择用于EBV选择性肿瘤细胞毒性的最佳核苷抗病毒药物。将在人EBV+癌症的小鼠模型中测试所选诱导剂与最佳抗病毒剂的组合。其结果将是一种更有效，选择性和更广泛的治疗EBV+癌症和LPD的方法。公共卫生相关性：潜伏性EB病毒（EBV）与许多人类恶性肿瘤和淋巴增殖性疾病相关，目前对其几乎没有有效的治疗方法。我们已经开发了一种新的病毒靶向治疗方法，将一种诱导病毒潜伏期的药物与一种获批的抗病毒药物组合，以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著疗效。我们在这里提出，以确定一个更有效的和优化的诱导剂和抗病毒剂，并证明他们的抗肿瘤活性的动物模型。