Biological Validation of Candidate Myeloma Driver Genes

项目摘要 我们在阐明多发性骨髓瘤（MM）遗传变化的能力方面取得了前所未有的进展， 候选驱动基因的名单，迫切等待生物验证-不仅是为了提高我们的 了解MM的自然史和遗传基础，同时优先考虑分子靶点 用于新的骨髓瘤治疗和预防。我们将采用新开发的，全面的临床前 深入评估候选骨髓瘤驱动因素的研究策略，从长远来看，该驱动因素似乎非常有希望 翻译的角度：叉头框M1转录因子，FOXM 1。 本研究的长期目标是改善骨髓瘤和相关浆细胞的预后， 肿瘤。主要目的是阐明假定的骨髓瘤驱动因素，如 FOXM 1，促进肿瘤的发生、耐药性的获得和难治性疾病的复发。的 中心假设是骨髓瘤驱动因素增加了致瘤性、克隆形成性和治疗抗性 因此，为骨髓瘤的新方法提供了合理的分子靶点 治疗和预防。三个具体的研究目标已被设计来测试这一假设， 实现本申请的目的。 目的1中的研究将评估FOXM 1在骨髓瘤生物学和遗传学中的作用。的 实验策略包括在含有升高水平的抗肿瘤药物的骨髓瘤细胞中评价药物应答。 FOXM 1和FOXM 1依赖性肿瘤进展的临床研究。预期成果包括 有证据表明FOXM 1是新治疗方法的一个有价值的目标，包括FDA批准的 毒品目标2中的研究将确定FOXM 1是否驱动肿瘤浆细胞的发展， 实验室老鼠实验策略依赖于确定小鼠中的肿瘤发病率和发作 用携带高水平FOXM 1的转基因B淋巴细胞重建。此外，还包括FOXM 1- 使用荷瘤小鼠进行的靶向治疗研究。预期成果包括支持 FOXM 1促进骨髓瘤发展并部分决定了 骨髓瘤细胞目标3中的研究将评估骨髓瘤中FOXM 1的遗传网络。的 实验策略包括确定骨髓瘤中FOXM 1依赖的基因表达变化 细胞和骨髓瘤基因组中FOXM 1结合位点的定位。预期成果包括 增加对FOXM 1促进肿瘤性浆细胞的机制的基于网络的理解 发展 支持强有力的初步结果，提供了一个健全的理由，这一应用，建议 研究准备促进治疗和预防多发性骨髓瘤的新靶向方法。

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.