BETR Therapy for Herpesvirus-Associated Tumors
BETR 治疗疱疹病毒相关肿瘤
基本信息
- 批准号:8043619
- 负责人:
- 金额:$ 55.35万
- 依托单位:
- 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 2014-02-28
- 项目状态:已结题
- 来源:
- 关键词:90YAffectAggressive courseAnimal ModelB-Cell LymphomasB-LymphocytesBeta ParticleBortezomibBurkitt LymphomaCarcinomaCause of DeathCell surfaceCellsClinicDrug KineticsEBV-associated malignancyEffectivenessEnzymesFire - disastersGanciclovirGenesGenomeHerpes Simplex InfectionsHerpesviridaeHerpesvirus 1Hodgkin DiseaseHuman Herpesvirus 4ImageInfectionInvestigationLeadLibrariesLymphomaLytic PhaseMS4A1 geneMalignant NeoplasmsMediatingMetabolicMolecularMolecular WeightMonoclonal AntibodiesMorbidity - disease rateNasopharynx CarcinomaNoseOrganOutcomePatientsPeripheralPhosphorylationPositron-Emission TomographyRadiationRadiation therapyRadioimmunoconjugateRadioisotopesRadiolabeledRadiopharmaceuticalsRefractoryRelapseRelative (related person)Stomach CarcinomaSubstrate SpecificityT-Cell LymphomaTargeted RadiotherapyTechniquesTestingTherapeuticTherapeutic StudiesThymidine KinaseTimeTissuesToxic effectTranslatingTumor TissueVelcadeViralViral GenomeVirusY 90 Ibritumomab Tiuxetanbasecancer imagingcancer therapycell typechimeric antibodydesigndosimetryfialuridinegene therapyimprovediodine-131-tositumomabkillingsmalignant stomach neoplasmmanmortalityneoplastic cellnovel strategiesolder patientpilot trialprospectivepublic health relevanceradiotracerrituximabsuccessthymidine kinase 1tositumomabtumoruptake
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.
PUBLIC HEALTH RELEVANCE:
Certain cancers, including lymphoma, nasopharyngeal carcinoma, gastric cancer and others, are often associated with viruses, in particular, the Epstein-Barr virus (EBV). We can harness an enzyme produced by EBV, the viral thymidine kinase (TK), to effect a new type of targeted therapy that employs a radiotherapeutic version of the viral TK substrate, namely, [131I]FIAU. Because EBV is often latent within the tumor, it must be activated by treatment with bortezomib. We will treat patients with EBV-associated lymphoma and nasopharygeal carcinoma with bortezomib then image them with [124I]FIAU and positron emission tomography, using the imaging to guide treatment with [131I]FIAU. This is a prospective, pilot trial of Bortezomib-induced Enzyme-Targeted Radiation (BETR) therapy in patients with relapsed/refractory EBV-associated malignancy.
描述(由申请人提供):
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RICHARD Frederick AMBINDER其他文献
RICHARD Frederick AMBINDER的其他文献
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{{ truncateString('RICHARD Frederick AMBINDER', 18)}}的其他基金
Investigating the EBV methylome in PLWH: Discovery and Development of Novel EBV Diagnostics in Plasma and Saliva
研究 PLWH 中的 EBV 甲基化组:血浆和唾液中新型 EBV 诊断的发现和开发
- 批准号:
10755171 - 财政年份:2023
- 资助金额:
$ 55.35万 - 项目类别:
Clonal Immunoglobulin DNA and Lymphoma Diagnosis
克隆免疫球蛋白 DNA 和淋巴瘤诊断
- 批准号:
9927306 - 财政年份:2020
- 资助金额:
$ 55.35万 - 项目类别:
Hodgkin Lymphoma in PLWH in South Africa: TB, EBV, and Tumor Molecular Markers
南非 PLWH 霍奇金淋巴瘤:TB、EBV 和肿瘤分子标记
- 批准号:
10377440 - 财政年份:2020
- 资助金额:
$ 55.35万 - 项目类别:
Hodgkin Lymphoma in PLWH in South Africa: TB, EBV, and Tumor Molecular Markers
南非 PLWH 霍奇金淋巴瘤:TB、EBV 和肿瘤分子标记
- 批准号:
10824451 - 财政年份:2020
- 资助金额:
$ 55.35万 - 项目类别:
Hodgkin Lymphoma in PLWH in South Africa: TB, EBV, and Tumor Molecular Markers
南非 PLWH 霍奇金淋巴瘤:TB、EBV 和肿瘤分子标记
- 批准号:
10681861 - 财政年份:2020
- 资助金额:
$ 55.35万 - 项目类别:
Hodgkin Lymphoma in PLWH in South Africa: TB, EBV, and Tumor Molecular Markers
南非 PLWH 霍奇金淋巴瘤:TB、EBV 和肿瘤分子标记
- 批准号:
10613422 - 财政年份:2020
- 资助金额:
$ 55.35万 - 项目类别:
Plasma and serum biomarkers for Hodgkin lymphoma
霍奇金淋巴瘤的血浆和血清生物标志物
- 批准号:
8913087 - 财政年份:2014
- 资助金额:
$ 55.35万 - 项目类别:
Plasma and serum biomarkers for Hodgkin lymphoma
霍奇金淋巴瘤的血浆和血清生物标志物
- 批准号:
8771661 - 财政年份:2014
- 资助金额:
$ 55.35万 - 项目类别:
Molecular Imaging in the Treatment of Kaposi's Sarcoma
分子影像治疗卡波西肉瘤
- 批准号:
8566681 - 财政年份:2012
- 资助金额:
$ 55.35万 - 项目类别:
BETR Therapy for Herpesvirus-Associated Tumors
BETR 治疗疱疹病毒相关肿瘤
- 批准号:
8233508 - 财政年份:2010
- 资助金额:
$ 55.35万 - 项目类别:
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