Biology of Multiple Myeloma Stem Cells

多发性骨髓瘤干细胞的生物学

基本信息

批准号：
7015625
负责人：
WILLIAM H MATSUI
金额：
$ 13.85万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-10 至 2010-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The immediate and long-term goals of the principal investigator are to become an independent clinical scientist with the ability to integrate and utilize biologically relevant findings from both clinical trials and correlative laboratory studies to develop innovative and effective therapies for multiple myeloma (MM). Therefore, the principal investigator proposes to undertake a career development plan that provides training in both clinical and laboratory research as well as the opportunity to implement these skills in a fully integrated research program. The application proposes an orderly series of research endeavors that will take advantage of the unique academic setting and provide invaluable experience in translational science as well as an organized educational program designed to formally train the principal investigator in clinical research. Furthermore, the expertise of the mentor and the highly conducive environment for developing and carrying out novel clinical anticancer strategies will facilitate the principal investigator's transition to independence. MM is characterized by the accumulation of malignant plasma cells that form the bulk of the tumor mass. However, these cells are relatively quiescent suggesting that the proliferative capacity of the tumor lies within a specialized subpopulation of cells, MM stem cells or progenitors that are responsible for the initiation and progression of disease by maintaining the production of new tumor cells. Our preliminary data demonstrate that MM stem cells resemble B cells rather than plasma cells and have the capacity to self-renew and produce progeny that subsequently differentiate into mature non-dividing plasma cells. A better understanding of the biology of MM stem cells is critical as therapies that inhibit their self-renewal may limit the production of new tumor cells. Conversely, treatments that affect mature plasma cells may induce clinical remissions, but cannot be potentially curative unless they also impact upon malignant progenitors. We hypothesize that the study of MM stem cells through a combination of clinical trials and correlative laboratory studies will provide continuous insight into the biology of MM and form the basis for novel therapies in MM. Accordingly, the specific aims of this proposal are to: (1) isolate and study the biology of MM stem cells; (2) develop further clinical strategies to target MM stem cells; and (3) Determine the effects of clinically targeting MM stem cells using monoclonal antibodies against antigens expressed on MM stem cells. Both clinical outcomes and laboratory correlates will be integrated to serve as the foundation for the development of subsequent generations of clinical trials.

描述（由申请人提供）：主要研究者的近期和长期目标是成为一名独立的临床科学家，有能力整合和利用临床试验和相关实验室研究的生物学相关发现，开发创新和有效的治疗方法多发性骨髓瘤（MM）。因此，主要研究者建议实施一项职业发展计划，提供临床和实验室研究方面的培训，以及在完全综合的研究计划中实施这些技能的机会。该申请提出了一系列有序的研究工作，这些工作将利用独特的学术环境，提供转化科学方面的宝贵经验，以及旨在正式培训临床研究主要研究者的有组织的教育计划。此外，导师的专业知识以及开发和实施新型临床抗癌策略的高度有利的环境将有助于首席研究员向独立的过渡。 MM 的特征是恶性浆细胞积聚，形成肿瘤块的大部分。然而，这些细胞相对静止，表明肿瘤的增殖能力存在于特殊的细胞亚群、MM干细胞或祖细胞中，它们通过维持新肿瘤细胞的产生而负责疾病的发生和进展。我们的初步数据表明，MM 干细胞类似于 B 细胞而不是浆细胞，并且具有自我更新和产生后代的能力，这些后代随后分化为成熟的非分裂浆细胞。更好地了解 MM 干细胞的生物学特性至关重要，因为抑制其自我更新的疗法可能会限制新肿瘤细胞的产生。相反，影响成熟浆细胞的治疗可能会引起临床缓解，但不可能具有潜在的治愈作用，除非它们也影响恶性祖细胞。我们假设，通过临床试验和相关实验室研究相结合对多发性骨髓瘤干细胞的研究将为多发性骨髓瘤的生物学提供持续的见解，并为多发性骨髓瘤新疗法奠定基础。因此，本提案的具体目标是：（1）分离并研究MM干细胞的生物学特性； (2) 制定针对MM干细胞的进一步临床策略； (3) 确定使用针对 MM 干细胞表达的抗原的单克隆抗体在临床上靶向 MM 干细胞的效果。临床结果和实验室相关性将被整合起来，作为后续几代临床试验开发的基础。