Overcoming IMiD resistance in Myeloma

项目总结 新药已经将多发性骨髓瘤(MM)从晚期血癌转变为多发性骨髓瘤，影响了大约 在美国，有8.3万人对一种疾病的靶向治疗有反应。最有效的MM之一 治疗方法是免疫调节(IMID)与脑白蛋白结合的药物(如来那度胺、泊马度胺)。这些 IMID抑制关键的MM细胞促生存干扰素调节因子4/骨髓瘤病病毒癌基因 (IRF4/MYC)途径通过促进脑白蛋白(CRBN)介导的IRF4降解间接实现 转录调控因子，Ikaros(IKZF1)。尽管大多数患者最初对IMiD治疗有反应，但耐药性是 无可避免。一种机制涉及CRBN活性的降低，这似乎是由于遗传 改变或修饰CRBN和IKZF1的表达。第二种机制涉及上调 CD44是透明质酸的主要细胞表面受体，参与MM细胞的黏附。到目前为止，还没有批准 治疗多发性骨髓瘤的药物被认为可以调节CD44和IRF4/MYC，这两个因子是IMiD抵抗的关键介质。药效 多发性骨髓瘤的耐药性似乎也涉及表观遗传修饰，影响小非编码蛋白的表达 RNAs(miRNAs，miRs)和药物转运蛋白。我们的临床前研究显示，泛组蛋白AR-42 去乙酰酶抑制剂，通过上调miRNAs下调IRF4/MYC途径和CD44的表达 协同增强IMIDD抗MM活性。我们首次在人类中进行AR-42复发的单剂试验 MM证明该制剂是安全的，有一些延长的临床反应。我们的中心假设是 AR-42通过上调降低CD44表达的miRNAs使MM细胞对IMiD治疗敏感(因此 药物外流)，并抑制IRF4/MYC途径。为了进一步检验我们的中心假设，重要的是 确定CD44是否在IMiD抵抗中发挥作用，以及miRNA调节是否可以绕过基因 与阻力相关的IMID靶的变化，以便：(A)了解表面的功能作用 可作为治疗靶点和/或用作抗IMiD标记的蛋白质；及(B)确定 MiRNAs有可能用于治疗，以克服IMiD耐药机制。我们的团队 将追求以下特定目标：1)研究CD44在体外和体外MM IMiD抵抗中的作用 活体；2)在IMiD治疗中通过miRs研究CD44和IRF4/MYC的调节；以及3)进行1b期 AR-42+泊马度胺治疗耐来那度胺的MM患者的研究结果：我们的研究将定义 黑色素瘤CD44表达、细胞内IMiD水平与IMiD抵抗的关系 多发性骨髓瘤患者血清sCD44水平是否为早期临床有价值的无创性指标 评估IMiD耐药性的发展，以指导临床医生在复发前改变治疗方法 正在发生。对miRNA调节的IMiD抗性的更好的理解将支持未来 旨在优化多发性骨髓瘤和其他多种疾病的IMiDS疗效和持续时间的临床研究 癌症。

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.