Biology of Multiple Myeloma Stem Cells

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，能够整合和利用临床试验和相关实验室研究的生物学相关结果，以开发多发性骨髓瘤（MM）的创新和有效疗法。 因此，主要研究者建议进行职业发展计划，提供临床和实验室研究方面的培训，以及在完全整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，并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，导师的专业知识和开发和实施新型临床抗癌策略的高度有利的环境将促进主要研究者向独立性的过渡。 MM的特征在于恶性浆细胞的积聚，其形成肿瘤块的大部分。 然而，这些细胞是相对静止的，表明肿瘤的增殖能力存在于特定的细胞亚群、MM干细胞或祖细胞中，这些细胞通过维持新肿瘤细胞的产生而负责疾病的起始和进展。 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，所述后代随后分化成成熟的非分裂浆细胞。 更好地了解MM干细胞的生物学是至关重要的，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诱导临床缓解，但除非它们也影响恶性祖细胞，否则不能潜在治愈。 我们假设，通过临床试验和相关实验室研究的结合对MM干细胞的研究将提供对MM生物学的持续了解，并形成MM新疗法的基础。因此，本提案的具体目标是：（1）分离和研究MM干细胞的生物学;（2）开发针对MM干细胞的进一步临床策略;和（3）使用抗MM干细胞上表达的抗原的单克隆抗体确定临床靶向MM干细胞的效果。 临床结果和实验室相关性将被整合，作为后续临床试验开发的基础。

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.