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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

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）：