Targeting Genomic Instability and Evolution in Myeloma

项目总结（见说明）： 多发性骨髓瘤（MM）的一个突出特征是显著的基因组不稳定性，这导致遗传变化，从而导致获得耐药性和疾病进展。因此，一个新兴的研究重点是确定与疾病进展相关的遗传变化的分子基础。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。我们还将开发基于抑制这些潜在机制的治疗策略，以避免或延迟基因组变化及其后遗症。在初步研究中，我们已经评估了同源重组（HR）作为MM中基因组不稳定性机制的作用。我们已经观察到：与正常浆细胞相比，MM细胞中的HR活性显著更高; MM细胞系和原代患者MM细胞随着时间推移获得更新的遗传变化; HR活性的抑制减少了新遗传变化的获得;相反，HR的诱导导致MM中遗传不稳定性增加，与耐药性的发展相关。这些和其他初步数据构成了我们假设的基础，即HR升高介导MM中的DNA不稳定性，因此可能有助于耐药性和疾病进展的发展，从而为靶向HR的新疗法提供了框架。在本项目中，我们将研究与诊断相比复发时发生的基因组变化，并评估其临床意义（Sp Aim 1）。我们将评估HR升高（基因组不稳定性的关键介质）作为预后标志物的作用（Sp Aim 2），并在临床前评估HR抑制剂预防基因组变化演变的能力（Sp Aim 3）。拟议的研究将提高我们对MM进展的理解，并可能促进疾病进展的预后测试的发展，以及识别新的治疗策略。

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.