Growth Control in Multiple Myeloma

多发性骨髓瘤的生长控制

基本信息

批准号：
8128506
负责人：
BART BARLOGIE
金额：
$ 365.33万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-06-05 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8128506
关键词：
Accounting Address Affect Allogenic Anabolic Agents Antibodies Basic Science Binding Biological Biological Models Bone Diseases Bone Formation Stimulation Bone Marrow Bortezomib Cadherins Cell Adhesion Cell Line Cell-Mediated Cytolysis Cells Clinical Clinical Research Clinical Trials Coculture Techniques Collaborations Combined Modality Therapy Development Dexamethasone Disease Disease remission Dose Drug Combinations Environment Event Exhibits Extramedullary Funding Future Gene Expression Profiling Genes Genetic Heterogeneity Goals Growth Human Activities Image Immunotherapeutic agent In Vitro Individual Interleukin-15 Intervention K-562 K562 Cells Knowledge Lead Lesion Light Longitudinal Studies Lytic Lytic Metastatic Lesion Maintenance Mediating Melphalan Membrane Modeling Molecular Monoclonal Antibodies Monoclonal gammopathy of uncertain significance Morbidity - disease rate Multiple Myeloma Mus Natural History Natural Killer Cells Neoplasm Metastasis Newly Diagnosed Osteoblasts Osteoclasts Osteogenesis Osteolytic Outcome Pathogenesis Pathway interactions Patients Peptide Hydrolases Placenta Plasma Cells Platelet Factor 4 Predisposition Protocols documentation Randomized Recruitment Activity Recurrent disease Refractory Regimen Relapse Research Research Personnel Residual state Resistance Resource Sharing Risk Role Sampling Scientist Serine Protease Signal Transduction Site Specific qualifier value Stem cells T-Lymphocyte Testing Thalidomide Therapeutic Therapy Clinical Trials Time Toxic effect Transfusion Translating Translational Research Transplantation Tumor Burden Work arm base beta catenin bone cell growth cytotoxic disorder later incidence prevention disorder risk effective therapy exhaust follow-up high risk humanized monoclonal antibodies imprint improved in vivo indexing innovation insight killings lenalidomide neoplastic cell novel novel therapeutic intervention outcome forecast patient population prevent programs repository success synergism treatment strategy tumor tumor growth

Accounting Address Affect Allogenic Anabolic Agents Antibodies Basic Science Binding Biological Biological Models Bone Diseases Bone Formation Stimulation Bone Marrow Bortezomib Cadherins Cell Adhesion Cell Line Cell-Mediated Cytolysis Cells Clinical Clinical Research Clinical Trials Coculture Techniques Collaborations Combined Modality Therapy Development Dexamethasone Disease Disease remission Dose Drug Combinations Environment Event Exhibits Extramedullary Funding Future Gene Expression Profiling Genes Genetic Heterogeneity Goals Growth Human Activities Image Immunotherapeutic agent In Vitro Individual Interleukin-15 Intervention K-562 K562 Cells Knowledge Lead Lesion Light Longitudinal Studies Lytic Lytic Metastatic Lesion Maintenance Mediating Melphalan Membrane Modeling Molecular Monoclonal Antibodies Monoclonal gammopathy of uncertain significance Morbidity - disease rate Multiple Myeloma Mus Natural History Natural Killer Cells Neoplasm Metastasis Newly Diagnosed Osteoblasts Osteoclasts Osteogenesis Osteolytic Outcome Pathogenesis Pathway interactions Patients Peptide Hydrolases Placenta Plasma Cells Platelet Factor 4 Predisposition Protocols documentation Randomized Recruitment Activity Recurrent disease Refractory Regimen Relapse Research Research Personnel Residual state Resistance Resource Sharing Risk Role Sampling Scientist Serine Protease Signal Transduction Site Specific qualifier value Stem cells T-Lymphocyte Testing Thalidomide Therapeutic Therapy Clinical Trials Time Toxic effect Transfusion Translating Translational Research Transplantation Tumor Burden Work arm base beta catenin bone cell growth cytotoxic disorder later incidence prevention disorder risk effective therapy exhaust follow-up high risk humanized monoclonal antibodies imprint improved in vivo indexing innovation insight killings lenalidomide neoplastic cell novel novel therapeutic intervention outcome forecast patient population prevent programs repository success synergism treatment strategy tumor tumor growth

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项目摘要

DESCRIPTION (provided by applicant): The overall objective of this program project is to understand MM growth in the context of its interaction with the bone marrow microenvironment (ME) in order to translate and exploit this knowledge into smarter MM growth control in patients. A concerted effort by a team of basic and clinical scientists is aimed at further overcoming the tremendous obstacles posed by MM's extensive genetic heterogeneity. We hypothesize that MM subjugates various ME components, perhaps in a MM subtypespecific manner, and that such MM-induced ME imprints may become an irreversible force contributing to MM's defiance of cure. In light of our theme of growth control in MM, toward achieving cure in an increasingly higher proportion of patients, investigators of 4 projects and 5 cores will continue to collaborate in a highly integrated and synergistic fashion. Project 1 plans to achieve better growth control via risk-based treatment strategies in an effort to reduce treatment-related toxicities in low-risk disease while accelerating outcome improvement in high-risk disease. Translational work will interrogate the MM-ME interaction and elucidate, through examination of serial gene expression profiling (GEP) samples, how this interaction affects growth control. Project 2 postulates to achieve better growth control in the relapsed setting by optimizing the clinical activity of haplo-identical NK cells via combination therapy with bortezomib and CS1 antibody. Basic research will examine the antimyeloma activity of human NK cells activated/expanded with K562 cells transfected with membrane-bound interleukin-15 (IL-15) and the co-stimulatory molecule 4-1BBL, in combination with bortezomib and CS1 Ab, in a murine model. Projects 3 and 4 deal with the role of bone, disease in MM pathogenesis. Project 3 will focus on fundamental observations relevant to DKK1 suppression of Wnt/beta-catenin signaling and the interaction of beta-catenin/cadherin cell adhesion with focal lesions, osteolytic bone disease, and MM dissemination to extramedullary disease, in an effort to harness the molecular MM-ME interaction therapeutically pertinent to MM pathogenesis, allowing us to investigate growth control via another avenue (by reduction of tumor cell adhesion). Project 4 will shed light on the biological mechanisms by which osteoblasts and osteoclasts affect myeloma cell growth and dissemination. By unraveling the consequences of altered activities of osteoclasts and osteoblasts on MM dissemination, and understanding the mechanisms involved, novel therapeutic interventions for MM can be developed. This work will be accomplished with access to 5 shared resource cores.

描述（由申请人提供）：该计划项目的总体目的是在与骨髓微环境（ME）相互作用的背景下了解MM的增长，以将这些知识转化并利用患者的MM增长更明智。一个基本和临床科学家团队的一致努力旨在进一步克服MM广泛的遗传异质性带来的巨大障碍。我们假设MM可能以MM亚型的方式征服了各种ME组件，并且这种MM引起的我的烙印可能会成为有助于MM违反治疗的不可逆转力。鉴于我们在MM中的增长控制为主题，在越来越高的患者中获得治疗，4个项目和5个核心的调查人员将继续以高度整合和协同的方式进行合作。项目1计划通过基于风险的治疗策略实现更好的增长控制，以减少低风险疾病中与治疗相关的毒性，同时加快高危疾病的结果改善。翻译工作将通过检查序列基因表达分析（GEP）样本来询问MM-ME相互作用，并阐明这种相互作用如何影响生长控制。项目2通过与硼替佐米和CS1抗体的联合疗法优化了单倍型NK细胞的临床活性，以在复发环境中获得更好的生长控制。基础研究将检查与鼠模型中的bortezomib和CS1 AB结合使用，与膜结合的白介素15（IL-15）（IL-15）（IL-15）（IL-15）（IL-15）（IL-15）和共刺激分子4-1BBL一起激活/扩展的人NK细胞的抗乳腺癌活性。项目3和4处理骨骼的作用，疾病在MM发病机理中。 Project 3 will focus on fundamental observations relevant to DKK1 suppression of Wnt/beta-catenin signaling and the interaction of beta-catenin/cadherin cell adhesion with focal lesions, osteolytic bone disease, and MM dissemination to extramedullary disease, in an effort to harness the molecular MM-ME interaction therapeutically pertinent to MM pathogenesis, allowing us to investigate growth control via另一个途径（通过减少肿瘤细胞粘附）。项目4将阐明成骨细胞和破骨细胞影响骨髓瘤细胞生长和传播的生物学机制。通过揭示破骨细胞和成骨细胞对MM传播的影响的后果，并理解所涉及的机制，可以开发出新的MM治疗干预措施。这项工作将通过访问5个共享资源核心来完成。