Targeting Genomic Instability and Evolution in Myeloma

项目总结(见说明)： 多发性骨髓瘤(MM)的一个突出特征是基因组的显著不稳定，这会导致基因变化，导致获得耐药性和疾病的进展。因此，一个新出现的研究重点是确定与疾病进展相关的进化基因变化的分子基础。在这个项目中，我们将描述基因组不稳定性的分子机制和临床后果。我们还将在抑制这些潜在机制的基础上制定治疗策略，以避免或推迟基因组变化及其后遗症。在初步研究中，我们评估了同源重组(HR)作为MM基因组不稳定机制的作用。我们观察到：MM细胞中HR活性显著高于正常浆细胞；MM细胞系和原发患者MM细胞随着时间的推移获得新的基因变化；抑制HR活性减少新基因变化的获得；反过来，诱导HR导致MM遗传不稳定性增加，与耐药相关。这些和其他初步数据形成了我们假设的基础，即HR升高介导了MM的DNA不稳定，因此可能有助于耐药性的发展和疾病的进展，从而为在新的治疗方法中针对HR提供了框架。在这个项目中，我们将研究复发时与诊断时相比的基因组变化，并评估它们的临床意义(Sp目标1)。我们将评估HR升高的作用，它是基因组不稳定的关键介质，作为预后的标志(Sp目标2)，并在临床前评估HR抑制物阻止基因组变化演变的能力(Sp目标3)。拟议的研究将提高我们对多发性骨髓瘤进展的理解，并可能促进疾病进展的预后测试的发展，以及确定新的治疗策略。

PROJECT SUMMARY (See instructions): A prominent feature of multiple myeloma (MM) is significant genomic instability, which leads to genetic changes resulting in acquisition of drug resistance and progression of disease. An emerging focus of investigation has therefore been to define the molecular basis for evolving genetic changes associated with disease progression. In this Project, we will delineate molecular mechanisms and clinical consequences of genomic instability. We will also, develop therapeutic strategies based upon inhibiting these underlying mechanisms to avoid or delay genomic changes and their sequelae. In preliminary studies, we have evaluated the role of homologous recombination (HR) as a mechanism for genomic instability in MM. We have observed that: HR activity is significantly higher in MM cells compared to normal plasma cells; MM cell lines and primary patient MM cells acquire newer genetic changes overtime; inhibition of HR activity reduces acquisition of new genetic changes; and conversely, induction of HR leads to increased genetic instability in MM, associated with the development of drug resistance. These and other preliminary data form the basis for our hypothesis that elevated HR mediates DNA instability in MM and may therefore contribute to development of drug resistance and disease progression, thereby providing the framework for targeting HR in novel therapeutics. In this Project, we will investigate the genomic changes evolving at the time of relapse compared to diagnosis and evaluate their clinical significance (Sp Aim 1). We will evaluate the role of elevated HR, a key mediator of genomic instability, as a marker of prognosis (Sp Aim 2), and preclinically evaluate the ability of inhibitors of HR to prevent evolution of genomic changes (Sp Aim 3). The proposed studies will improve our understanding of progression of MM and may facilitate the development of prognostic tests for disease progression, as well as identity novel therapeutic strategies.