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

项目总结 这一职业过渡奖将使候选人能够实现她成为一名成功人士的职业目标 多发性骨髓瘤(MM)预防方面的独立研究员。这位候选人目前的研究计划是 重点阐述能量平衡因素对多发性骨髓瘤发病风险和生存的影响。这项研究建议在 这本K22将聚焦于未确定意义的单克隆性伽马病(MGUS)和阴燃MM (SMM)，这是癌前状态，在部分患者中进展为MM，原因如下 人们对此知之甚少。循证策略不能用于预防MGUS/SMM的进展到 嗯，强调了这方面研究的重要性。一种有希望的药物干预措施，以减少 MGUS/SMM进展为MM的风险是二甲双胍，一种廉价、安全、可广泛获得的药物 在实验室和流行病学研究中证明具有抗骨髓瘤的特性。研究假设是 二甲双胍的使用将与：(1)显著减少疾病的临床症状 进展，以及(2)与恶性转化有关的骨髓细胞表达改变 为了验证这些假说，我们将进行为期6个月的双盲安慰剂试验。 纳入86名目前没有癌症风险策略的MGUS/SMM患者的对照试验 还原。这项提案中概述的研究有望有助于临床研究范式的改变。 MGUS和SMM的后续行动，从观察和等待的方法，到侧重于预防和 疾病进展的拦截。补充这项研究的培训计划将提供 具备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的候选人 对多发性骨髓瘤和前驱多发性骨髓瘤患者采取有效的干预措施。具体地说，培训旨在 提供多发性骨髓瘤前体生物学、单细胞测序方法和干预的高级知识 在癌症预防研究中准备独立从事专注于预防的研究事业 创新的研究和战略培训活动将共同促进职业发展。 候选人的身份。

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.