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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：
8324018
负责人：
BART BARLOGIE
金额：
$ 362.76万
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/8324018
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）：该计划项目的总体目标是了解 MM 生长与骨髓微环境 (ME) 相互作用的背景，以便将这些知识转化和利用到患者更智能的 MM 生长控制中。基础和临床科学家团队的共同努力旨在进一步克服多发性骨髓瘤广泛的遗传异质性所带来的巨大障碍。我们假设 MM 可能以 MM 亚型特异性方式征服各种 ME 成分，并且这种 MM 诱导的 ME 印记可能成为导致 MM 抗拒治愈的不可逆转的力量。鉴于我们的多发性骨髓瘤生长控制主题，为了使越来越多的患者实现治愈，4个项目和5个核心的研究人员将继续以高度集成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生长控制，以减少低风险疾病中与治疗相关的毒性，同时加速高风险疾病的结果改善。转化工作将探究 MM-ME 相互作用，并通过检查连续基因表达谱 (GEP) 样本来阐明这种相互作用如何影响生长控制。项目 2 假设通过硼替佐米和 CS1 抗体的联合治疗优化单倍体相同 NK 细胞的临床活性，从而在复发环境中实现更好的生长控制。基础研究将在小鼠模型中检查用转染膜结合白细胞介素 15 (IL-15) 和共刺激分子 4-1BBL 的 K562 细胞激活/扩增的人类 NK 细胞的抗骨髓瘤活性，并结合硼替佐米和 CS1 Ab。项目 3 和 4 涉及骨骼、疾病在 MM 发病机制中的作用。项目 3 将重点关注与 DKK1 抑制 Wnt/β-连环蛋白信号传导以及 β-连环蛋白/钙粘蛋白细胞粘附与局灶性病变、溶骨性骨疾病和 MM 传播到髓外疾病的相互作用相关的基本观察，努力利用与 MM 发病机制相关的分子 MM-ME 相互作用进行治疗，使我们能够通过以下方式研究生长控制：另一种途径（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扩散的生物学机制。通过揭示破骨细胞和成骨细胞活性改变对 MM 传播的影响，并了解其中涉及的机制，可以开发新的 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。