Biology of Multiple Myeloma Stem Cells

描述(由申请人提供)：首席研究员的近期和长期目标是成为一名独立的临床科学家，有能力整合和利用来自临床试验和相关实验室研究的生物学相关发现，以开发多发性骨髓瘤(MM)的创新和有效治疗方法。因此，首席研究人员建议实施职业发展计划，提供临床和实验室研究方面的培训，并有机会在完全整合的研究计划中实施这些技能。 该申请提出了一系列有序的研究努力，将利用独特的学术环境，提供宝贵的翻译科学经验，以及旨在正式培训临床研究首席研究员的有组织的教育计划。此外，导师的专业知识和开发和执行新的临床抗癌策略的高度有利的环境将促进首席研究人员向独立的过渡。 多发性骨髓瘤的特点是恶性浆细胞的聚集，这些细胞构成了大部分肿瘤。然而，这些细胞相对静止，这表明肿瘤的增殖能力存在于特定的细胞亚群中，即MM干细胞或祖细胞，它们通过维持新的肿瘤细胞的产生而负责疾病的发生和发展。我们的初步数据表明，多发性骨髓瘤干细胞类似于B细胞，而不是浆细胞，具有自我更新和产生后代的能力，后代随后分化为成熟的未分裂的浆细胞。更好地了解多发性骨髓瘤干细胞的生物学是至关重要的，因为抑制其自我更新的治疗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导致临床缓解，但除非它们也对恶性前体细胞产生影响，否则不可能具有潜在的疗效。我们推测，通过临床试验和相关实验室研究相结合对MM干细胞的研究将为MM的生物学提供持续的洞察力，并为MM的新疗法奠定基础。因此，本建议的具体目标是：(1)分离和研究MM干细胞的生物学；(2)进一步开发针对MM干细胞的临床策略；以及(3)使用针对MM干细胞上表达的抗原的单抗来确定临床靶向MM干细胞的效果。临床结果和实验室相关性将被整合在一起，作为开发后续几代临床试验的基础。

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.