Growth Control in Multiple Myeloma

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）相互作用的背景下，以便将这些知识转化和利用为患者更智能的MM生长控制。基础和临床科学家团队的共同努力旨在进一步克服MM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亚型特异性的方式使各种ME成分屈服，并且这种MM诱导的ME印记可能成为导致MM无视治愈的不可逆力量。鉴于我们的MM生长控制主题，为了在越来越高比例的患者中实现治愈，4个项目和5个核心的研究者将继续以高度整合和协同的方式合作。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，以减少低风险疾病的治疗相关毒性，同时加速高风险疾病的结局改善。翻译工作将询问MM-ME相互作用，并通过检查系列基因表达谱（GEP）样品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CS 1抗体联合治疗优化单倍型相同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测用膜结合白细胞介素-15（IL-15）和共刺激分子4-1BBL转染的K562细胞激活/扩增的人NK细胞与硼替佐米和CS 1 Ab联合的抗骨髓瘤活性。项目3和项目4涉及骨疾病在MM发病机制中的作用。项目3将重点关注与DKK 1抑制Wnt/β-catenin信号传导以及β-catenin/cadherin细胞粘附与局灶性病变、溶骨性骨病和MM向髓外疾病的传播的相互作用相关的基本观察，以努力利用与MM发病机制相关的分子MM-ME相互作用，使我们能够通过另一种途径（通过减少肿瘤细胞粘附）研究生长控制。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。通过阐明破骨细胞和成骨细胞活性改变对MM播散的影响，并了解相关机制，可以开发MM的新型治疗干预措施。这项工作将通过访问5个共享资源核心来完成。

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.