Project 4: Targeting genomic instability and evolution in myeloma

项目摘要-项目4达纳-法伯癌症研究所 多发性骨髓瘤(MM)和其他恶性肿瘤的一个显著特征是显著的基因组不稳定导致 克隆进化和疾病进展。我们之前已经在多个版本中描述了突变的情况 多发性骨髓瘤(MM)的研究表明，突变的数量与MM的总体和无事件生存率相关。 在目前的资助期，我们使用深度WGS调查了183名新诊断的MM患者和 显示MM的突变负荷具有显著的变异性。此外，所有MM亚组均已激活 突变特征表明同源重组(HR)和NER功能障碍是一个突出的晚期 突变过程，而APOBEC信号在疾病进展的中间阶段被激活 重要的是，在高危多发性骨髓瘤中，DNA损伤程度低的亚组预后更好。我们最近的研究也 证明在大剂量治疗后复发时获得显著更高数量的突变 与RVD(3种药物的标准剂量组合)进行比较，并将HR功能障碍确定为显著的潜在原因 机制。这些观察结果也与我们之前的数据一致，这些数据表明HR是失调的 并对MM的基因组不稳定性和耐药性的发展有重要贡献。 基因组进化的潜在机制，我们还发现了一个影响DNA的激酶基因信号 包括MM在内的癌细胞的修复(尤其是HR)和基因组稳定性。我们进一步证明了PDZ 结合激酶(PBK)是该信号的成员之一，通过以下途径影响MM细胞的DNA修复和基因组稳定性 DNA修复基因和调控主要DNA的转录因子FOXM1的直接磷酸化 修复小路。基于这些和其他数据，我们假设MM基因组是由复杂的克隆定义的 在确诊时驱动疾病并在复发时进一步演变的结构，它是由失调的调节机制介导的 DNA修复及相关基因。为了达到这个目标，我们将研究诊断时骨髓瘤细胞克隆的复杂性。 和复发及其对预后的影响(特定目标1)；从功能上验证PDZ结合激酶(PBK)用于 它对MM细胞克隆进化、生长和存活的影响(特定目标2)；以及单独评估PBK抑制剂 并与现有的MM药物相结合，在体外和在MM的小鼠模型中(特异性目标3)。本研究 将提高我们对导致遗传不稳定、克隆进化和 多发性骨髓瘤的进展，并将确定抑制生长和预防/延迟的新靶点和治疗策略 疾病的演变。

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.