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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(申请人提供)：爱泼斯坦-巴尔病毒(EBV)与许多人类恶性肿瘤有关，目前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系统恶性肿瘤包括Burkitt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增生性疾病(LPD)。尤其是EBV(+)T和T/NK淋巴瘤通常预后不佳，如果是单克隆性的LPD也是如此。与潜伏EBV相关的实体肿瘤包括鼻咽癌(NPC)、胃癌和乳腺癌。EBV流行的关键是其保持休眠或“潜伏”状态的能力。EBV是一种疱疹病毒，许多疱疹病毒家族感染的细胞可以被核苷类抗病毒药物如更昔洛韦杀死，这些药物针对病毒胸苷激酶(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。我们已经在人类肿瘤细胞的体外试验中证明，在这些细胞中诱导EBV TK基因表达的选定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诱导剂联合更昔洛韦(IND#47,529)对15例EBV相关淋巴瘤或LPD患者的耐受性/毒性和疗效，这些患者对常规放疗和化疗都完全耐药。我们的靶向治疗取得了4/15患者的完全临床反应(CRS)和6例良好的部分反应(PR)(总有效率为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，而正常细胞幸免于难。因此，这种新的治疗策略确定了一个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诱导使细胞对传统的抗病毒药物敏感。该策略的独特特点包括分子靶点和方法的特异性(病毒阴性[正常]细胞将幸免)。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数天。这项提议将识别和测试更活跃的TK基因诱导剂，这种诱导剂可以在更方便的基础上使用，以改进这种有针对性的治疗方法。我们将特别关注短链脂肪酸衍生物(SCFAD)或HDAC抑制剂，这些药物已获批准或即将获得批准，具有优越的药代动力学，并且对EBV TK基因的作用比我们当前一代的药物更具选择性。我们还将为EBV选择性肿瘤细胞毒性选择最佳的核苷类抗病毒药物。选定的诱导剂将与最佳抗病毒药物一起在人类EBV+癌症的小鼠模型中进行测试。其结果将是对EBV+癌症和LPD的更有效、更有选择性和更广泛可接受的治疗。公共卫生相关性：潜伏的EB病毒(EBV)与许多人类恶性肿瘤和淋巴增生性疾病有关，目前对这些疾病几乎没有有效的治疗方法。我们开发了一种新的病毒靶向治疗方法，将一种诱导病毒走出潜伏期的药物与一种经批准的抗病毒药物相结合，用于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。我们建议寻找一种更有效和更优化的诱导剂和抗病毒药物，并在动物模型中展示它们的抗肿瘤活性。