Repurposing Metformin for the Prevention of Disease Progression in Precursor Multiple Myeloma

项目摘要 这个职业过渡奖将定位候选人，以实现她的职业目标，成为一个成功的 多发性骨髓瘤（MM）预防的独立研究者。候选人目前的研究计划是 集中于阐明能量平衡因素对MM风险和生存的影响。该研究在 K22将集中于意义不明的单克隆丙种球蛋白病（MGUS）和郁积型MM (SMM)，这是由于以下原因在一部分患者中进展为MM的癌前病变， 不太了解。没有循证策略可预防MGUS/SMM进展为 MM，强调了这一领域研究的重要性。一种有希望的药物干预， MGUS/SMM进展为MM的风险是二甲双胍，一种廉价、安全和广泛可用的药物 在实验室和流行病学研究中证明了其抗骨髓瘤特性。研究假设是 二甲双胍的使用将与：（1）疾病临床症状的显著减轻 进展，和（2）与恶性转化有关的骨髓小生境细胞的表达改变 为了检验这些假设，我们将进行一项为期6个月的双盲安慰剂试验， 对照试验入组了86例目前没有可用的癌症风险策略的MGUS/SMM患者 还原该提案中概述的研究预计将有助于改变临床 从观察和等待的做法，到侧重于预防和 阻止疾病进展。补充这项研究的培训计划将提供 候选人具有翻译病原学和流行病学发现所需的专业知识的深度和广度 对MM和MM前体患者进行有效干预。具体而言，培训旨在 提供前体MM生物学，单细胞测序方法和干预的先进知识 研究在癌症预防准备的独立职业生涯的研究重点是预防 创新研究和战略培训活动将共同促进职业发展 的候选人。

PROJECT SUMMARY This Career Transition Award will position the candidate to achieve her career goal of becoming a successful independent investigator in multiple myeloma (MM) prevention. The candidate's current program of research is focused on elucidating the impact of energy balance factors on MM risk and survival. The research proposed in this K22 will focus on monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), which are premalignant conditions that progress to MM in a subset of patients for reasons that are poorly understood. Evidence-based strategies are unavailable for preventing the progression of MGUS/SMM to MM, underscoring the importance of research in this area. A promising pharmacologic intervention to reduce the risk of progression of MGUS/SMM to MM is metformin, an inexpensive, safe, and widely-available drug with demonstrated anti-myeloma properties in laboratory and epidemiologic studies. The study hypothesis is that metformin use will be associated with: (1) a significant reduction in clinical symptoms of disease progression, and (2) altered expression of bone marrow niche cells implicated in the malignant transformation of MGUS/SMM to overt MM. To test these hypotheses, we will conduct a 6-month, double-blind placebo- controlled trial enrolling 86 MGUS/SMM patients who currently have no available strategies for cancer risk reduction. The research outlined in this proposal is expected to contribute to a paradigm change in the clinical follow-up of MGUS and SMM, from a watch and wait approach, to a paradigm focused on the prevention and interception of disease progression. The training plan that complements this research will provide the candidate with the depth and breadth of expertise needed to translate etiologic and epidemiologic discoveries into efficacious interventions for MM and precursor MM patients. Specifically, the training is designed to provide advanced knowledge of precursor MM biology, single-cell sequencing approaches, and intervention research in cancer prevention in preparation for an independent career of research focused on the prevention of MM. Together, the innovative research and strategic training activities will promote the career development of the candidate.