Virus-Targeted Therapy for Malignancies

描述（由申请人提供）：eb病毒（EBV）与许多人类恶性肿瘤有关，目前几乎没有有效的治疗方法。由爱泼斯坦-巴尔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和所有移植后淋巴增生性疾病（LPD）。EBV(+) T和T/NK淋巴瘤通常预后不良，单克隆的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流行的关键是其持续处于休眠或“潜伏”状态的能力。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抗病毒药物杀死，比如更昔洛韦，它的靶点是病毒胸苷激酶（TK）酶。然而，与疱疹病毒家族的其他成员不同，EBV对这些抗病毒药物具有耐药性，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实验中证明，在这些细胞中选择诱导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15例ebv相关淋巴瘤或LPD患者的tk诱导剂联合更昔洛韦（IND #47,529）的耐受性/毒性和疗效，这些患者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反应（cr），另外6例患者产生了良好的部分反应（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，正常细胞得以幸免。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传统的抗病毒药物敏感。该策略的独特特点包括分子靶标和方法的特异性（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许多天。该建议将鉴定和测试更多TK基因的活性诱导剂，这些诱导剂可以在更方便的基础上给药，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，它们具有更好的药代动力学，并且对EBV TK基因的作用比当前一代药物更具选择性。我们也将选择最佳的核苷抗病毒ebv选择性肿瘤细胞毒性。选定的诱导剂将与最佳抗病毒药物联合在人类EBV+癌症小鼠模型中进行测试。结果将是EBV+癌症和LPD的更有效，选择性和更广泛的治疗方法。

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.