Overcoming IMiD resistance in Myeloma

项目摘要 新的药物已经将多发性骨髓瘤（MM）从一种晚期血癌转变为一种晚期血癌， 在美国有83,000人，对靶向治疗有反应的疾病最有效的MM 治疗是免疫调节（IMiD）脑蛋白结合药物（例如来那度胺、泊马度胺）。这些 IMiD抑制关键MM细胞促生存干扰素调节因子4/髓细胞瘤病病毒癌基因 (IRF4/MYC）途径间接通过促进cereblon（CRBN）介导的IRF 4降解来实现。 转录调节子Ikaros（IKZF 1）。虽然大多数患者最初对IMiD治疗有反应，但耐药性仍存在。 不可避免的一种机制涉及CRBN活性的降低，这似乎是由于遗传因素引起的。 CRBN和IKZF 1的改变或修饰的表达。第二种机制涉及上调 CD 44是透明质酸的主要细胞表面受体，参与MM细胞粘附。到目前为止，没有批准 已知MM中使用的药物可调节IMiD耐药性的关键介质CD 44和IRF 4/MYC。药物 MM中的耐药性似乎也涉及表观遗传修饰，影响小的非编码基因的表达。 RNA（miRNAs，miRs）和药物转运蛋白。我们的临床前研究表明，AR-42，一种泛组蛋白， 去乙酰化酶抑制剂，通过miRNA上调下调IRF 4/MYC通路和CD 44表达 并协同增强IMiD抗MM活性。我们的第一个人类AR-42单药试验， MM证明该药物是安全的，具有一些延长的临床反应。我们的核心假设是， AR-42通过上调降低CD 44表达的miRNA（从而使MM细胞对IMiD治疗敏感）， 药物外排）并抑制IRF 4/MYC途径。为了进一步检验我们的中心假设， 确定CD 44是否在IMiD抗性中发挥功能性作用，以及miRNA调控是否可以绕过基因调控。 与耐药性相关的IMiD靶点的改变，以便：（a）了解表面的功能作用 可以治疗靶向和/或用作IMiD抗性标志物的蛋白质;和（B）确定 miRNA具有治疗性地用于克服IMiD抗性机制的潜力。我们的团队 1）研究CD 44在体外和体外MM IMiD耐药中的作用， 体内; 2）研究IMiD治疗通过miR对CD 44和IRF 4/MYC的调节;和3）进行1b期 AR-42+泊马度胺在来那度胺耐药MM患者中的研究。结果：我们的研究将定义 MM中CD 44表达、细胞内IMiD水平和IMiD耐药之间的关系。 MM患者血清中sCD 44水平是否是一个有价值的非侵入性标志物， 评估IMiD耐药性的发展，可指导临床医生在复发前改变治疗 正在发生对miRNA调控的IMiD耐药性的进一步了解将支持未来的研究。 旨在优化IMiD在MM和其他各种疾病中的疗效和缓解持续时间的临床研究 癌的

PROJECT SUMMARY New drugs have transformed Multiple Myeloma (MM) from a terminal blood cancer, affecting approximately 83,000 people in the U.S., to a disease responsive to targeted therapies. Among the most effective MM treatments are the immunomodulatory (IMiD) cereblon-binding drugs (e.g. lenalidomide, pomalidomide). These IMiDs inhibit the critical MM cell pro-survival interferon regulatory factor 4/myelocytomatosis viral oncogene (IRF4/MYC) pathway indirectly by promoting the cereblon (CRBN) mediated degradation of the IRF4 transcriptional regulator, Ikaros (IKZF1). Although most patients initially respond to IMiD therapy, resistance is inevitable. One mechanism involves a decrease of CRBN activity, which appears to be due to genetic alterations or modified expression of CRBN and IKZF1. The second mechanism involves upregulation of CD44, the main cell surface receptor for hyaluronan, involved in MM cell adhesion. Thus far, no approved agent used in MM is known to modulate CD44 and IRF4/MYC, the key mediators of IMiD resistance. Drug resistance in MM also seems to involve epigenetic modifications, affecting expression of small non-coding RNAs (miRNAs, miRs) and drug transporters. our preclinical studies revealed that AR-42, a pan-histone deacetylase inhibitor, downregulates the IRF4/MYC pathway and CD44 expression via miRNAs upregulation and synergistically enhances IMiD anti-MM activity. Our first in human, single agent trial of AR-42 in relapsed MM demonstrated the agent was safe with some prolonged clinical responses. Our central hypothesis is that AR-42 sensitizes MM cells to IMiD treatment by upregulating miRNAs that reduce CD44 expression (and thus drug efflux) and inhibit the IRF4/MYC pathway. To further test our central hypothesis, it is important to determine if CD44 is playing a functional role in IMiD resistance and if miRNA regulation can bypass genetic alterations in IMiD targets associated with resistance in order to: (a) understand a functional role of a surface protein that can be therapeutically targeted and/or used as a marker of IMiD resistance; and (b) establish if miRNAs have the potential to be used therapeutically to overcome mechanisms of IMiD resistance. Our team will pursue the following specific aims: 1) Investigate the role of CD44 in MM IMiD resistance in vitro and in vivo; 2) Investigate CD44 and IRF4/MYC regulation via miRs with IMiD therapy; and 3) Conduct a phase 1b study of AR-42+Pomalidomide in Lenalidomide-resistant MM patients. Outcomes: Our studies will define the relationship of CD44 expression, intracellular IMiDs levels, and IMiD resistance in MM. We will understand whether sCD44 level in the serum of MM patients is a valuable non invasive marker for an early clinical assessment of the development of IMiD resistance that could guide clinicians to change therapy before relapse is occurring. The improved understanding concerning miRNA-modulated IMiD resistance will support future clinical studies aimed at optimizing the efficacy and duration of response to IMiDs in MM and a variety of other cancers.