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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该职业转型奖将使候选人能够实现成为成功人士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重点阐明能量平衡因素对 MM 风险和生存的影响。该研究提出于该 K22 将重点关注意义未明的单克隆丙种球蛋白病 (MGUS) 和冒烟型 MM (SMM)，这是由于以下原因在一部分患者中进展为 MM 的癌前病症：不太了解。尚无基于证据的策略来预防 MGUS/SMM 进展为 MM，强调了该领域研究的重要性。一种有希望的药物干预措施，可减少 MGUS/SMM 进展为 MM 的风险在于二甲双胍，一种廉价、安全且广泛使用的药物在实验室和流行病学研究中已证明具有抗骨髓瘤特性。研究假设是二甲双胍的使用将与：(1) 疾病临床症状显着减轻进展，以及（2）与恶性转化有关的骨髓生态位细胞的表达改变 MGUS/SMM 到公开 MM。为了检验这些假设，我们将进行为期 6 个月的双盲安慰剂试验对照试验招募了 86 名目前没有可用的癌症风险策略的 MGUS/SMM 患者减少。该提案中概述的研究预计将有助于临床范式的改变 MGUS 和 SMM 的后续行动，从观察和等待方法到注重预防和预防的范式阻断疾病进展。补充本研究的培训计划将提供候选人具有转化病因学和流行病学发现所需的深度和广度的专业知识为 MM 和前期 MM 患者提供有效的干预措施。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高级知识癌症预防研究，为专注于预防的独立研究生涯做准备 MM的。创新研究和战略培训活动共同促进职业发展候选人的。