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

重新利用二甲双胍预防前体多发性骨髓瘤的疾病进展

• 批准号: 10249288
• 负责人: Catherine Marinac
• 金额: $ 19.22万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249288
• 关键词: Address; Area; Behavioral; Biology; Blood; Bone Marrow; Career Transition Award; Cells; Clinical; Clinical Management; Clinical Trials; Complement; Data; Data Collection; Development; Disease; Disease Progression; Early treatment; Enrollment; Ensure; Epidemiologist; Etiology; Foundations; Gene Expression; Goals; Immune; In Vitro; Individual; Infrastructure; Intercept; Intervention; Intervention Studies; Knowledge; Laboratory Study; Letters; Malignant - descriptor; Malignant Neoplasms; Measures; Metabolic Pathway; Metformin; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Non-Insulin-Dependent Diabetes Mellitus; Oncologist; Organ; Oxidative Phosphorylation; Patient observation; Patients; Pharmaceutical Preparations; Pharmacology; Placebos; Plasma Cell Neoplasm; Plasma Cells; Population; Positioning Attribute; Precancerous Conditions; Preparation; Prevention; Prevention strategy; Property; Randomized; Research; Research Personnel; Risk; Risk Reduction; Scientist; Serum; Survival Rate; Symptoms; Testing; Training; Training Activity; Translating; Tumor Markers; antitumor effect; arm; base; burden of illness; cancer prevention; cancer risk; career; career development; clinically relevant; clinically significant; cohort; cost; cost effective; design; disorder prevention; double-blind placebo controlled trial; efficacious intervention; efficacy testing; energy balance; epidemiologic data; epidemiologic discoveries; epidemiology study; evidence base; follow-up; high risk; improved; in vivo; innovation; interest; mTOR Signaling Pathway; milligram; multiple myeloma M Protein; neoplastic cell; non-diabetic; novel; novel strategies; patient population; patient subsets; premalignant; prevent; programs; recruit; reduce symptoms; response; single cell sequencing; single-cell RNA sequencing; standard of care; transcriptomics; tumor-immune system interactions

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.

项目摘要 该职业过渡奖将使候选人确定成为成功的职业目标 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 专注于阐明能量平衡因素对MM风险和生存的影响。该研究提出了 该K22将重点放在不确定意义（MGU）和闷烧的MM的单克隆伽马病上 （SMM），这是预先态度的，由于原因是，在一部分患者中，其原因是 理解不佳。基于证据的策略无法防止MGU/SMM的发展 MM，强调了该领域研究的重要性。一种有希望的药理干预措施来减少 MGU/SMM向MM进展的风险是二甲双胍，一种便宜，安全且可用的药物 在实验室和流行病学研究中证明了抗肌瘤特性。研究假设是 二甲双胍的使用将与：（1）疾病的临床症状大大减少 进展，（2）改变了与恶性转化有关的骨髓细胞的表达 mgus/smm的明显mm。为了检验这些假设，我们将进行6个月的双盲安慰剂 - 对照试验招募了86名MGU/SMM患者，他们目前没有可用的癌症风险策略 减少。预计该提案中概述的研究将导致临床的范式变化 从手表和等待方法到范式的MGUS和SMM的后续措施，重点是预防和 疾病进展的拦截。补充这项研究的培训计划将为 具有深度和广度的候选人，需要翻译病因和流行病学发现 进入MM和前体MM患者的有效干预措施。具体来说，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 预防癌症预防的研究，以准备专注于预防的独立研究职业 mm。创新的研究和战略培训活动一起将促进职业发展 候选人。