Project 4: Targeting genomic instability and evolution in myeloma

项目 4：针对骨髓瘤的基因组不稳定性和进化

• 批准号: 10555734
• 负责人: Nikhil C. Munshi
• 金额: $ 31.35万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555734
• 关键词: Architecture; Automobile Driving; Cell Survival; Cells; Characteristics; Clonal Evolution; Code; Color; Complex; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Pathway; Dana-Farber Cancer Institute; Data; Diagnosis; Disease; Disease Progression; Disease-Free Survival; Dose; Evolution; FOXM1 gene; Frequencies; Functional disorder; Funding; Genes; Genetic; Genome; Genome Stability; Genomic Instability; Genomic approach; Genomics; Goals; Growth; Heterogeneity; In Vitro; Left; Malignant Neoplasms; Mediating; Modeling; Multiple Myeloma; Mutation; Newly Diagnosed; Normal Cell; Outcome; PDZ-binding kinase; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphotransferases; Process; Relapse; Reporting; Role; Sampling; Single base substitution; Subgroup; Therapeutic; Time; cancer cell; cancer genomics; cell behavior; cell growth; cell type; chemotherapy; drug resistance development; drug standard; epigenomics; genetic signature; genome-wide; high risk; homologous recombination; improved; in vivo; kinase inhibitor; loss of function; member; mouse model; novel; premalignant; prevent; repaired; timeline; transcription factor; transcriptomics

Project Summary – Project 4 Dana-Farber Cancer Institute A prominent feature of multiple myeloma (MM) and other malignancies is significant genomic instability leading to clonal evolution and disease progression. We have previously described the mutational landscape in multiple myeloma (MM) and shown that the number of mutations correlates with overall and event free survival in MM. In the current funding period, using deep WGS, we investigated 183 newly diagnosed patients with MM and demonstrated a significant variability in mutational load in MM. Moreover, all MM subgroups had activated mutational signatures indicative of homologous recombination (HR) and NER dysfunction as a prominent late mutational process, whereas APOBEC signature is activated in the intermediate phase of disease progression in high-risk MM. Importantly, a subgroup with low DNA damage had a superior outcome. Our recent studies also demonstrate the acquisition of significantly higher number of mutations at relapse following high-dose therapy compared to RVD (a 3-drug standard-dose combination) and identify HR dysfunction as a prominent underlying mechanism. These observations are also consistent with our previous data which show that HR is dysregulated and significantly contributes to genomic instability and development of drug resistance in MM. Investigating the mechanisms underlying genomic evolution, we have also identified a kinase gene signature impacting DNA repair (especially HR) and genome stability in cancer cells including MM. We further demonstrate that PDZ Binding Kinase (PBK), a member of this signature, impacts DNA repair and genome stability in MM cells through direct phosphorylation of DNA repair genes and that of a transcription factor FOXM1, which regulates major DNA repair pathways. Based on these and other data, we hypothesize that MM genome is defined by complex clonal architecture that drives the disease at diagnosis and evolves further at relapse and it is mediated by dysregulated DNA repair and related genes. Towards this goal, we will investigate myeloma cell clonal complexity at diagnosis and relapse and their impact on outcome (Specific Aim 1); functionally validate PDZ Binding Kinase (PBK) for its impact on MM cell clonal evolution, growth and survival (Specific Aim 2); and evaluate PBK inhibitors, alone and in combination with existing MM drugs, in vitro and in murine models of MM (Specific Aim 3). This study will improve our understanding of mechanisms which contribute to genetic instability, clonal evolution and progression in MM and will identify novel targets and therapeutic strategies to inhibit growth and prevent/delay evolution of the disease.

项目概要-项目4丹娜-法伯癌症研究所 多发性骨髓瘤（MM）和其他恶性肿瘤的一个突出特征是显著的基因组不稳定性， 克隆进化和疾病进展的关系我们先前已经描述了多个突变景观 在骨髓瘤（MM）中，突变的数量与MM的总体生存期和无事件生存期相关。 在当前的资助期内，使用深度WGS，我们调查了183例新诊断的MM患者， 显示MM中突变负荷的显著变异性。此外，所有MM亚组均激活了 指示同源重组（HR）和NER功能障碍的突变特征是一个突出的晚期 突变过程，而APOBEC签名在疾病进展的中间阶段被激活 重要的是，低DNA损伤的亚组具有更好的上级结果。我们最近的研究也 证明在高剂量治疗后复发时获得显著更高数量的突变 与RVD（3种药物标准剂量复方制剂）相比，并将HR功能障碍确定为一种突出的基础疾病 机制这些观察结果也与我们以前的数据一致，这些数据表明HR失调 并显著促进MM的基因组不稳定性和耐药性的发展。 基因组进化的潜在机制，我们还确定了一个激酶基因签名影响DNA 修复（特别是HR）和基因组稳定性的癌细胞，包括MM。我们进一步证明，PDZ 结合激酶（PBK）是该特征的一员，通过以下途径影响MM细胞中的DNA修复和基因组稳定性： DNA修复基因的直接磷酸化和调节主要DNA的转录因子FOXM 1的直接磷酸化 修复路径。基于这些和其他数据，我们假设MM基因组是由复杂的克隆 在诊断时驱动疾病并在复发时进一步演变的结构，它是由失调介导的 DNA修复及相关基因为了实现这一目标，我们将研究诊断时骨髓瘤细胞克隆的复杂性 和复发及其对结果的影响（具体目标1）;功能验证PDZ结合激酶（PBK）， 其对MM细胞克隆进化、生长和存活的影响（具体目标2）;以及单独评估PI 3 K抑制剂 以及与现有MM药物组合，在体外和MM的鼠模型中（具体目标3）。本研究 将提高我们对遗传不稳定性，克隆进化和 MM的进展，并将确定新的靶点和治疗策略，以抑制生长和预防/延迟 疾病的演变。