Growth Control in Multiple Myeloma

描述(由申请人提供)： 该计划项目的总体目标是在与骨髓微环境(ME)相互作用的背景下了解MM生长，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。一个由基础和临床科学家组成的团队共同努力，旨在进一步克服多发性骨髓瘤广泛的遗传异质性带来的巨大障碍。我们假设MM可能以MM亚型特异性的方式征服各种ME成分，并且这种MM诱导的ME印记可能成为导致MM反抗治愈的不可逆转的力量。根据我们在MM中控制生长的主题，为了在越来越高的患者比例中实现治愈，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战略实现更好的增长控制，以努力减少低风险疾病与治疗相关的毒性，同时加快改善高风险疾病的结果。翻译工作将询问MM-ME相互作用，并通过对系列基因表达谱(GEP)样本的检查，阐明这种相互作用如何影响生长控制。项目2假定通过与Bortezomib和CS1抗体的联合治疗来优化单倍体相合的NK细胞的临床活性，从而在复发情况下实现更好的生长控制。基础研究将在小鼠模型中检测K562细胞激活/扩增的人NK细胞的抗骨髓瘤活性。K562细胞转染膜结合的白介素15(IL-15)和共刺激分子4-1BBL，与Bortezomib和CS1 Ab相结合。项目3和4涉及骨病在多发性骨髓瘤发病机制中的作用。项目3将集中于与Dkk1抑制Wnt/β-catenin信号相关的基础观察，以及β-catenin/cadherin细胞与局灶性病变、溶骨性骨病和MM向髓外疾病扩散的相互作用，以努力利用MM-ME相互作用在治疗上与MM发病相关，使我们能够通过另一种途径(通过减少肿瘤细胞黏附)来研究生长控制。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。通过揭示破骨细胞和成骨细胞活性改变对多发性骨髓瘤扩散的影响，并了解其中涉及的机制，可以开发新的多发性骨髓瘤的治疗干预措施。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.