BETR Therapy for Herpesvirus-Associated Tumors

BETR 治疗疱疹病毒相关肿瘤

基本信息

批准号：
8447549
负责人：
RICHARD Frederick AMBINDER
金额：
--
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8447549
关键词：
90Y Affect Aggressive course Animal Model B-Cell Lymphomas B-Lymphocytes Beta Particle Bortezomib Burkitt Lymphoma Carcinoma Cause of Death Cell surface Cells Clinic Drug Kinetics EBV-associated malignancy Effectiveness Enzymes Fire - disasters Ganciclovir Genes Genome Herpes Simplex Infections Herpesviridae Herpesvirus 1 Hodgkin Disease Human Herpesvirus 4 Image Infection Investigation Lead Libraries Lymphoma Lytic Phase MS4A1 gene Malignant Neoplasms Mediating Metabolic Molecular Molecular Weight Monoclonal Antibodies Morbidity - disease rate Nasopharynx Carcinoma Nose Organ Outcome Patients Peripheral Phosphorylation Positron-Emission Tomography Radiation Radiation therapy Radioimmunoconjugate Radioisotopes Radiolabeled Radiopharmaceuticals Refractory Relapse Relative (related person)Stomach Carcinoma Substrate Specificity T-Cell Lymphoma Targeted Radiotherapy Techniques Testing Therapeutic Therapeutic Studies Thymidine Kinase Time Tissues Toxic effect Translating Tumor Tissue Velcade Viral Viral Genome Virus Y 90 Ibritumomab Tiuxetan base cancer imaging cancer therapy cell type chimeric antibody design dosimetry fialuridine gene therapy improved iodine-131-tositumomab killings malignant stomach neoplasm man mortality neoplastic cell novel strategies older patient pilot trial prospective public health relevance radiotracer rituximab success thymidine kinase 1 tositumomab tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Great strides have been made in the management of lymphoma with therapies tailored to particular cell types, e.g., those expressing the B cell surface molecule CD20. Monoclonal antibodies and radioimmunoconjugates such as [131I]Tositumomab (Bexxar") and [90Y]ibritumomab iuxetan (Zevalin") have led to therapeutic successes with less therapy-associated morbidity and mortality. Nevertheless, lymphoma is the cause of death for at least 20,000 people annually in the US, providing impetus for the search for new approaches to target tumor cells selectively. Since its discovery in association with Burkitt's lymphoma, Epstein-Barr Virus (EBV) has been found in association with a variety of lymphomas and other tumors, including gastric and nasopharyngeal carcinoma. Some of these lymphomas are among the very most refractory to standard therapies. Nasal-type NK lymphoma, EBV-associated peripheral T cell lymphoma and EBV-associated Hodgkin's lymphoma in older patients stand out from other lymphomas for their aggressive courses. We propose a radionuclide-based therapy for EBV-associated malignancies that relies on the metabolic concentration of a radiolabeled low molecular weight substrate in tumors mediated by the EBV thymidine kinase (TK). The approach that we will employ is also in analogy with ganciclovir-based gene therapy, except that we can omit the gene tagging step because tumor cells harboring the EBV genome will already possess the TK that we can harness for targeted, enzymatic radiotherapy. Because the substrate specificity for the viral TK is orthogonal to that of cellular TK, we can use a radiotherapeutic version of the virus-specific TK substrate, 2'-fluoro-2'-deoxy-1-2-D-arabinofuranosyl-5-iodouracil (FIAU), to effect this therapy. Because the viral genome is latent, it must be activated using a pharmacologic inducer such as bortezomib. We have already successfully administered [124I]FIAU to patients with infection for imaging non-cellular (bacterial) TK and have already determined, from a library of over 3,000 tested compounds, that bortezomib (Velcade) was most potent at activating the viral lytic cycle, and therefore TK, within infected cells. We have recently shown in animal models that Bortezomib-induced Enzyme-Targeted Radiotherapy (BETR) was capable of halting the progression of or eliminating EBV-associated tumors. Here we will translate this promising experimental technique to the clinic by performing careful dosimetry studies, using FIAU-PET, which will be used to guide an initial therapeutic study in lymphoma. We anticipate that this enzyme-mediated molecular radiotherapy, which we will use here to treat herpesvirus-associated tumors, will encourage further investigation into the activation of tissue-specific enzymes for cancer imaging and therapy.

描述（由申请人提供）：在淋巴瘤的管理中已经取得了长足的进步，该疗法量身定制为特定细胞类型的疗法，例如表达B细胞表面分子CD20的疗法。单克隆抗体和放射免疫共轭物，例如[131i] tositumomab（Bexxar“）和[90y] ibritumomomab Iuxetan（Zevalin”），导致了治疗成功的疗法成功，而与治疗相关的发病率和死亡率较低。然而，在美国，淋巴瘤是每年至少有20,000人死亡的原因，这为寻找新方法选择靶向肿瘤细胞提供了动力。自从发现与伯基特淋巴瘤相关的发现以来，Epstein-Barr病毒（EBV）与各种淋巴瘤和其他肿瘤有关，包括胃癌和鼻咽癌。这些淋巴瘤中的一些是对标准疗法最难治性的之一。鼻型NK淋巴瘤，与EBV相关的周围T细胞淋巴瘤和与EBV相关的Hodgkin淋巴瘤在老年患者中脱颖而出，从其他淋巴瘤中脱颖而出。我们提出了一种基于放射性核素的治疗，用于与EBV相关的恶性肿瘤，该治疗依赖于由EBV胸苷激酶（TK）介导的肿瘤中放射性标记的低分子量底物的代谢浓度。我们将采用的方法也类似于基于Ganciclovir的基因治疗，但我们可以省略基因标记步骤，因为携带EBV基因组的肿瘤细胞已经拥有我们可以利用的TK，用于靶向酶散射疗法。由于病毒TK的底物特异性与细胞TK的底物特异性是正交的，因此我们可以使用病毒特异性TK底物的放射治疗版本，2'-氟-2'-二氧基-1-2-D-DEOXY-1-2-D-D-D-D-D-D-D-D-D- ARABINOPURANOSYL-5-5-5-二氧化碳（FIAU），以实现这种治疗。由于病毒基因组是潜在的，因此必须使用诸如硼替佐米的药理学诱导剂进行激活。我们已经成功地为感染的患者施用了[124i] FIAU，用于成像非细胞（细菌）TK，并且已经从3,000多个经过测试化合物的库中确定了硼替佐米（Velcade）（Velcade）在激活病毒周期中最有效的，因此在受感染的细胞中最有效。我们最近在动物模型中表明，硼替佐米诱导的酶靶向放射疗法（BETR）能够停止或消除与EBV相关的肿瘤的进展。在这里，我们将使用FIAU-PET进行仔细的剂量学研究将这种有希望的实验技术转化为诊所，该研究将用于指导淋巴瘤的初步治疗研究。我们预计，这种酶介导的分子放疗，我们将在这里用来治疗与疱疹病毒相关的肿瘤，它将鼓励进一步研究组织特异性酶进行癌症成像和治疗的激活。