MENTORING AND RESEARCH IN CANCER STEM CELLS

 描述(申请人提供)：癌症干细胞(CSCs)已在广泛的人类恶性肿瘤中被发现，它们增强的生长潜力表明在癌症的发生、维持、复发和进展中发挥着重要作用。然而，在CSC假说成为癌症患者治疗的基础之前，必须解决的关键差距是缺乏证明CSC具有临床重要性的数据，以及缺乏临床适用的靶向策略。这一K24奖项的候选人是约翰·霍普金斯大学的副教授，他已经开始建立一个专注于CSCs的翻译和临床研究计划，并在以患者为导向的研究、同行评议的资助和成功的指导方面建立了良好的记录。该小组最初在多发性骨髓瘤(MM)中分离CSCs，确定了新的CSC靶向策略，将这些实验室发现转化为创新的临床试验，并开发了新的生物标记物来量化临床环境中的CSCs。这项研究极大地提高了关于CSCs的基本知识，并领导了测试其临床意义的努力。这个项目成功的一个关键部分是在以患者为中心的研究中对年轻和早期研究人员的指导和培训。具体地说，候选人一直致力于为获得和掌握技能提供指导，以根据重要的临床问题制定重要和创新的假设，执行健全和严格的科学调查以破译疾病发病机制和开发新的治疗方法，将这些发现转化为临床试验，并在临床环境中针对原始假设进行有意义的相关性研究。通过这项K24申请，候选人寻求支持和受保护的时间，以提高他的指导技能，扩大他的研究专长。在指导方面，他将实施一项深思熟虑的教学课程工作计划，一位资深学术领袖的指导，以及在拟议研究计划的背景下指导他的受训者的结构化计划。关于新的研究技能，候选人将在实现拟议的具体目标的同时，通过与领先的生物信息学专家进行课程作业和监督培训，获得一个新领域--生物信息学的专业知识。最后，候选人将通过探索肿瘤微环境和通过下一代序列分析探索MM CSCs中的特定基因变化来扩大他的研究计划。这项研究的目的将导致新的生物标志物的开发，可以作为CSCs的替代品，并解决CSCs与临床结果相关的假设。第二个假设是，基于这些实验方法的新的治疗靶点可以靶向多发性骨髓间充质干细胞。因此，这项建议的科学目标是(1)确定多发性骨髓间充质干细胞的临床相关性和(2)确定抑制多发性骨髓间充质干细胞的新策略。这些培训和科学努力将显著扩大候选人的研究计划，并提高他的指导技能，以进一步建立以CSC为重点的以患者为导向的研究的领先和范式转换计划。

 DESCRIPTION (provided by applicant): Cancer stem cells (CSCs) have been identified in wide range of human malignancies, and their enhanced growth potential suggests a major role in cancer initiation, maintenance, relapse, and progression. However, the scarcity of data demonstrating CSCs are clinically important and the lack of clinically applicable targeting strategies are the critical gaps that must be addressed before the CSC hypothesis can become a basis for the treatment of cancer patients. The candidate for this K24 award is an Associate Professor at Johns Hopkins University who has begun to build a translational and clinical research program focused on CSCs and has established a strong track record of patient-oriented research, peer-reviewed funding, and successful mentoring. This group originally isolated CSCs in multiple myeloma (MM), identified novel CSC-targeting strategies, translated these laboratory findings into innovative clinical trials, and developed novel biomarkers to quantify CSCs in the clinical setting. This research has significantly advanced basic knowledge regarding CSCs and led efforts to test their clinical significance. A critical part of the success f this program has been the mentoring and training of young and early investigators in patient-oriented research. Specifically, the candidate has been committed to providing guidance for the acquisition and mastery of skills to formulate significant and innovative hypotheses from important clinical questions, execute sound and rigorous scientific inquiry to decipher disease pathogenesis and develop novel therapeutic approaches, translate these findings into clinical trials, and carry out meaningful correlative studies addressing the original hypothesis in the clinical setting. Through this K24 application, the candidate seeks support and protected time to improve his mentoring skills and expand his research expertise. In terms of mentoring, he will carry out a deliberate plan of didactic course work, mentorship from a senior academic leader, and a structured plan of mentoring his trainees within the context of the proposed research plan. With respect to new research skills, the candidate will gain expertise in a new area, bioinformatics, through coursework and supervised training with leading bioinformatics experts while carrying out the proposed Specific Aims. Finally, the candidate will expand his research program by exploring the tumor microenvironment and probing specific genetic changes within MM CSCs through next generation sequence analysis. The research Aims will lead to the development of new biomarkers that can act as surrogates for CSCs and address the hypothesis that CSCs correlate with clinical outcomes. A second hypothesis is that novel therapeutic targets based on these experimental approaches can target MM CSCs. Accordingly; the scientific Aims of this proposal are to (1) determine the clinical relevance of MM CSCs and (2) identify novel strategies to inhibit MM CSCs. These training and scientific endeavors will significantly expand the candidate's research program and improve his mentorship skills to further build a leading and paradigm-shifting program in CSC-focused patient oriented research.