Validation of FOXM1 as a new therapeutic target in high-risk myeloma

项目摘要 尽管血癌研究取得了巨大进展，但治疗和预防多发性骨髓瘤的能力， 在美国，第二常见的血液病，仍然非常有限。这是特别的 对于被诊断为高危骨髓瘤的患者子集来说是真的。解决目前的限制将需要 其他研究努力，包括关于最近发现的候选人生物学意义的项目 高危骨髓瘤驱动因子，如叉头盒M1转录因子FOXM1。 这项研究计划的长期目标是改善骨髓瘤和相关浆细胞的预后。 肿瘤。在这里提出的具体研究项目的主要目的是阐明这一机制。 通过FOXM1增强骨髓瘤的侵袭性。中心假设是FOXM1驱动和 为高危骨髓瘤提供了一个有希望的治疗机会。有两个具体的研究目标 旨在检验这一假设，并实现这一应用程序的目标。 AIM 1的研究将使用人骨髓瘤细胞系和患者来源的骨髓瘤细胞来评估 FOXM1在骨髓瘤生物学(如克隆生长和存活)和骨髓瘤遗传学(如FOXM1)中的作用 靶基因和药物敏感性)。实验策略包括可诱导的上调或下调 骨髓瘤细胞中的FOXM1，FOXM1控制的基因网络的芯片序列分析，以及 骨髓瘤细胞中FOXM1在疾病进展过程中的水平。 AIM 2上的研究将确定FOXM1是否在遗传学上驱动肿瘤浆细胞的发育 人类骨髓瘤的基因工程小鼠模型。另一个目标涉及FOXM1的相关性 小鼠骨髓瘤样瘤对小分子FOXM1和蛋白酶体抑制剂的反应状况。 实验策略包括过继转移表达基因标记的B淋巴细胞 人类FOXM1水平升高。还包括临床前治疗研究，在这些研究中 骨髓瘤样瘤对蛋白酶体的抑制作用将被评估。 有强有力的初步结果支持，这些结果为这项申请提供了充分的理由，拟议的 研究正准备促进新的有针对性的方法来治疗高危多发性骨髓瘤。

Project Summary Despite enormous progress in blood cancer research, the ability to treat and prevent multiple myeloma, the second most common hematologic cancer in the United States, remains severely limited. This is particularly true for the subset of patients diagnosed with high-risk myeloma. Addressing the current limitations will require additional research efforts, including projects on the biological significance of recently discovered candidate high-risk myeloma drivers, such as the forkhead box M1 transcription factor, FOXM1. The long-term goal of this research program is to improve the outcome of myeloma and related plasma cell neoplasms. The main objective of the specific research project proposed here is to elucidate the mechanism by which FOXM1 enhances the aggressiveness of myeloma. The central hypothesis is that FOXM1 drives and affords a promising treatment opportunity for high-risk myeloma. Two specific Research Aims have been designed to test this hypothesis and achieve the objective of this application. The studies in Aim 1 will employ human myeloma cell lines and patient-derived myeloma cells to assess the role of FOXM1 in myeloma biology (e.g., clonogenic growth and survival) and myeloma genetics (e.g., FOXM1 target genes and drug sensitivity). The experimental strategy includes the inducible up or down regulation of FOXM1 in myeloma cells, ChIP-seq analysis of the FOXM1-governed gene network, and the determination of FOXM1 levels in myeloma cells in the course of disease progression. The studies in Aim 2 will determine whether FOXM1 drives neoplastic plasma cell development in a genetically engineered mouse model of human myeloma. An additional objective concerns the correlation of FOXM1 status of myeloma-like tumors in mice with the response to small-molecule FOXM1 and proteasome inhibitors. The experimental strategy includes the adoptive transfer of genetically tagged B-lymphocytes that express elevated levels of human FOXM1. Also included are preclinical treatment studies in which the response of myeloma-like tumors to proteasome inhibition will be assessed. 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 of high-risk multiple myeloma.