Biological Validation of Candidate Myeloma Driver Genes

候选骨髓瘤驱动基因的生物学验证

• 批准号: 10437328
• 负责人: Siegfried Janz
• 金额: $ 19.26万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437328
• 关键词: Autologous Stem Cell Transplantation; B-Lymphocytes; Binding Sites; Biological; Biology; Cell Line; Cells; Chromosomal translocation; Clinical; Clinical Research; Clinical Trials; Cytogenetics; Data; Development; Disease; Dose; Drug Evaluation; Drug resistance; FDA approved; FOXM1 gene; Gene Expression; Genes; Genetic; Genome; Goals; Hematologic Neoplasms; Hematopoietic Neoplasms; Human; Incidence; Iowa; Laboratory mice; Malignant - descriptor; Malignant Neoplasms; Measures; Medical; Modality; Modeling; Molecular Genetics; Molecular Target; Multiple Myeloma; Mus; Mutation; Natural History; Neoplasms; Neoplastic Plasma Cell; Network-based; Newly Diagnosed; Oncogenes; Oncology Group; Outcome; Patients; Pharmaceutical Preparations; Plasma Cell Neoplasm; Plasma Cells; Prevention; Prognosis; Proteasome Inhibitor; Refractory Disease; Regulation; Relapse; Research; Research Project Grants; Resistance; Resolution; Risk; Role; Solid; Testing; Transgenic Organisms; Translations; Tumorigenicity; Universities; Validation; Work; acquired drug resistance; candidate validation; design; disorder risk; drug relapse; epigenome; genetic testing; high risk; high risk population; human model; improved outcome; inhibitor/antagonist; innovation; insight; mouse model; multidisciplinary; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; plasma cell development; pre-clinical; pre-clinical research; reconstitution; response; risk stratification; small molecule; sound; stemness; targeted treatment; transcription factor; tumor; tumor progression

Project Summary Unprecedented progress in our ability to elucidate genetic changes in multiple myeloma (MM) has led to long lists of candidate driver genes that are urgently awaiting biological validation – not only to enhance our understanding of the natural history and genetic underpinnings of MM, but also to prioritize molecular targets for new myeloma therapies and preventions. We will employ a newly developed, comprehensive preclinical research strategy to evaluate in-depth a candidate myeloma driver that appears to be very promising from a translational point of view: the forkhead box M1 transcription factor, FOXM1. The long-term goal of this research is to improve the outcome of myeloma and related plasma cell neoplasms. The main objective is to elucidate the mechanism by which putative myeloma drivers, such as FOXM1, promote tumor development, acquisition of drug resistance and relapse with refractory disease. The central hypothesis is that myeloma drivers increase the tumorigenicity, clonogenicity and therapy resistance of malignant plasma cells and, therefore, provide a rational molecular target for new approaches to myeloma treatment and prevention. Three Specific Research Aims have been designed to test this hypothesis and achieve the objective of this application. The studies in Aim 1 will evaluate the role of FOXM1 in myeloma biology and genetics. The experimental strategy includes the evaluation of drug responses in myeloma cells containing elevated levels of FOXM1 and clinical studies on FOXM1-dependent tumor progression. The anticipated outcome includes evidence that FOXM1 is a worthy target of new treatment approaches that include repurposed FDA-approved drugs. The studies in Aim 2 will determine whether FOXM1 drives neoplastic plasma cell development in laboratory mice. The experimental strategy relies on the determination of tumor incidence and onset in mice reconstituted with transgenic B-lymphocytes that harbor elevated levels of FOXM1. Also included are FOXM1- targeted treatment studies using tumor -bearing mice. The anticipated outcome includes support for the contention that FOXM1 promotes myeloma development and determines, in part, the drug response of myeloma cells. The studies in Aim 3 will assess the genetic network of FOXM1 in myeloma. The experimental strategy involves the determination of FOXM1-dependent gene expression changes in myeloma cells and the mapping of FOXM1 binding sites in the myeloma genome. The anticipated outcome includes increased network-based understanding of the mechanism by which FOXM1 promotes neoplastic plasma cell development. Supported by strong preliminary results that provide a sound rationale for this application, the proposed research is poised to facilitate novel targeted approaches to the therapy and prevention of multiple myeloma.

项目概要 我们在阐明多发性骨髓瘤 (MM) 基因变化的能力方面取得了前所未有的进展，这导致了长期 迫切等待生物学验证的候选驱动基因列表——不仅是为了增强我们的 了解 MM 的自然史和遗传基础，同时优先考虑分子靶标 新的骨髓瘤治疗和预防。我们将采用新开发的综合临床前 深入评估候选骨髓瘤驱动因素的研究策略，该驱动因素似乎非常有希望 翻译观点：叉头盒M1转录因子，FOXM1。 这项研究的长期目标是改善骨髓瘤和相关浆细胞的治疗结果 肿瘤。主要目标是阐明假定的骨髓瘤驱动因素的机制，例如 FOXM1，促进肿瘤发展、耐药性的获得和难治性疾病的复发。这 中心假设是骨髓瘤驱动因素增加致瘤性、克隆性和治疗耐药性 因此，为治疗骨髓瘤的新方法提供了合理的分子靶点 治疗和预防。设计了三个具体的研究目标来检验这一假设 达到本应用的目的。 目标 1 中的研究将评估 FOXM1 在骨髓瘤生物学和遗传学中的作用。这 实验策略包括评估含有升高水平的骨髓瘤细胞的药物反应 FOXM1 和 FOXM1 依赖性肿瘤进展的临床研究。预期成果包括 有证据表明 FOXM1 是新治疗方法的一个有价值的目标，其中包括 FDA 批准的重新用途 药物。目标 2 中的研究将确定 FOXM1 是否驱动肿瘤性浆细胞的发育 实验室小鼠。实验策略依赖于小鼠肿瘤发生率和发作的确定 用含有升高水平的 FOXM1 的转基因 B 淋巴细胞重建。还包括 FOXM1- 使用荷瘤小鼠进行靶向治疗研究。预期成果包括支持 FOXM1 促进骨髓瘤发展并部分决定药物反应的争论 骨髓瘤细胞。目标 3 中的研究将评估 FOXM1 在骨髓瘤中的遗传网络。这 实验策略涉及确定骨髓瘤中 FOXM1 依赖性基因表达变化 细胞和骨髓瘤基因组中 FOXM1 结合位点的定位。预期成果包括 增加基于网络的对 FOXM1 促进肿瘤性浆细胞机制的理解 发展。 得到强有力的初步结果的支持，为本申请提供了合理的理由，拟议的 研究旨在促进治疗和预防多发性骨髓瘤的新的靶向方法。