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）：Epstein-Barr病毒（EBV）与目前几乎没有有效治疗的许多人类恶性肿瘤有关。由爱泼斯坦 - 巴尔病毒引起的淋巴病恶性肿瘤包括伯基特的淋巴瘤，T/NK淋巴瘤，一些T-和B细胞淋巴瘤，大约一半的霍奇金淋巴瘤以及所有后移植型淋巴细胞增生性疾病（LPD）。 EBV（+）T和T/NK淋巴瘤通常具有不祥的预后，而LPD也是单克隆的。与潜在EBV有关的实体瘤包括鼻咽癌（NPC），胃癌和乳腺癌。 EBV患病率的关键是它在休眠状态或“潜在”状态下持续存在的能力。 EBV是一种疱疹病毒，许多疱疹家庭感染的细胞可以被核苷类似物抗病毒药（如ganciclovir）杀死，该药物的靶向病毒性胸苷激酶（TK）酶。但是，与疱疹病毒家族的其他成员不同，EBV对这些抗病毒剂具有抵抗力，因为潜在感染的细胞不表达病毒（TK）酶。我们已经在对人类肿瘤细胞的体外测定中进行了证明，这些肿瘤细胞选择了这些细胞中诱导EBV TK基因表达的药物使它们容易受到标准抗病毒药物的影响。然后，我们进行了I/II期研究并发表了一项I/II期研究，以确定15例与EBV相关的淋巴瘤或LPD患者的TK诱导剂加上Ganciclovir（IND＃47,529）的耐受性/毒性和功效，所有这些患者均完全抵抗常规辐射和化学疗法。我们的目标疗法在4/15例患者中产生了完整的临床反应（CRS），并在另外6例患者中产生了良好的部分反应（PRS）（总反应率为67％）。这是一种真正的靶向疗法，因为只有肿瘤细胞（包含EBV）被杀死 - 普通细胞被保留。因此，这种新型的治疗策略因此确定了仅存在于肿瘤细胞中的一种新靶（癌症相关病毒），并利用病毒蛋白的药理学诱导使细胞易受传统的抗病毒剂的影响。该策略的独特特征包括分子靶标和该方法的特异性（病毒阴性[正常]细胞将被保留。当前治疗方案的唯一主要限制是，用于在医院中诱导连续IV输液的药物必须通过连续诱导病毒给予，这一建议将在许多天内确定和测试，以进一步确定和测试，这可以提高the the The The The The The The The The The The The The The Tingk Genee，这可以使TK Genee降低，并且可以使TK Genee降低，这一建议将得到更多的目标，并且可以使THE的范围进行，从而可以提出更多的目标。治疗方法。在人类EBV+癌症的小鼠模型中，最佳的抗病毒剂将是对EBV+癌症和LPD的更有效，选择性和更广泛的治疗。公共卫生相关性：潜在的爱泼斯坦 - 巴尔病毒（EBV）与许多人类恶性肿瘤和淋巴增殖性疾病有关，目前几乎没有有效的治疗方法。我们已经开发了一种新型病毒靶向的治疗方法，结合了一种药物，将病毒与批准的抗病毒剂一起诱导病毒，以治疗这些恶性肿瘤和淋巴样增殖性疾病，并在I/II期临床试验中证明了安全性和显着的功效。我们在这里建议确定一种更有效，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。