The Role of Cereblon Pathways in Myeloma

描述（由申请人提供）：临床研究证明免疫调节药物（IMiDs）治疗多发性骨髓瘤（MM）的显着疗效。事实上，沙利度胺及其结构类似物来那度胺和波马度胺是每年销售额达数十亿美元的药物。然而，只有15-30%的复发患者对单一药物有反应，大多数对治疗有反应的患者最终产生获得性耐药。我们研究了沙利度胺的主要靶点小脑（CRBN）在IMiDs抗mm活性中的功能作用，并证明CRBN对沙利度胺、波马度胺和来那度胺的抗癌和免疫活性是绝对必需的。我们最近在高度耐药患者中首次发现了CRBN基因组失活突变，并证明CRBN基因表达水平可以预测接受IMiDs的MM患者的反应和生存结果。我们和其他人发现干扰素调节因子4 （IRF4）是crbn相关信号传导的关键下游靶点之一，与IMiD耐药相关。因此，CRBN-IRF4轴是开发新疗法的靶标，在血液恶性肿瘤和免疫系统操纵中具有广泛的应用。这些发现以及我们团队已经开发的临床、细胞和分子工具包为开发临床反应预测因子和识别靶标（不仅包括CRBN本身，还包括其下游效应物）打开了大门

DESCRIPTION (provided by applicant): Clinical studies have demonstrated the remarkable efficacy of immunomodulatory drugs (IMiDs) for the treatment of Multiple Myeloma (MM). Indeed, Thalidomide and its structural analogs Lenalidomide and Pomalidomide are drugs with billions of dollars in sales annually. However only 15-30% of relapsed patients respond to single agent drug and a majority of those patients who respond to treatment eventually develop acquired drug resistance. We have investigated the functional role of cereblon (CRBN), a primary target of Thalidomide, in the anti-MM activity of IMiDs and demonstrated that CRBN is absolutely required for the anti- cancer and immune activity of Thalidomide, Pomalidomide and Lenalidomide. We recently identified the first genomic inactivating mutations in CRBN in highly drug resistant patients and have demonstrated that gene expression levels of CRBN can predict response and survival outcomes in MM patients receiving IMiDs. We and others identified interferon regulatory factor 4 (IRF4) as one of the key downstream targets of CRBN-associated signaling, associated with IMiD drug resistance. Thus the CRBN-IRF4 axis is a target for development of new therapeutics with broad application in hematologic malignancies and immune system manipulation. These findings and the clinical, cellular and molecular toolkits already developed by our team open the door to development of clinical predictors of response and the identification of targets including not only CRBN itself, but also its downstream effectors to overcome IMiD resistance. The three aims of this study are: 1. We will construct a 635 patient tissue microarray (TMA) and use quantitative AQUA immunoflourescence (IF) or IHC to validate effectors of IMiD drug resistance. 2. In a prospective clinical trial in IMiD refractory Myeloma we will generate data on the frequency of CRBN pathway mutation contributing to drug resistance. 3. We will integrate genome wide RNA interference screening and MS proteomics to identify novel targets downstream of CRBN as potential entry points in the future development of therapeutics.