Novel nucleotide-based approaches targeting the STAT3 pathway for the treatment of lymphoma

项目摘要 非霍奇金淋巴瘤（NHL）是一组异质性疾病，主要是B细胞起源。NHL发病率为 逐渐增加，使其成为美国第六大最常见的癌症，估计有超过70，000例新发 2015年的案件。NHL的范围从惰性到侵袭性癌症，如弥漫性大B细胞淋巴瘤， 活化B细胞样型（ABC-DLBCL）。越来越多的证据表明，B细胞淋巴瘤患者的生存率低， 免疫抑制持续激活信号转导和转录激活因子3（STAT 3）。在 ABC-DLBCL，基因突变增强Toll样受体9（TLR 9）/MyD 88信号传导，从而导致 在淋巴瘤细胞和肿瘤相关免疫系统中诱导STAT 3活化的细胞因子的分泌 细胞，如骨髓来源的抑制细胞（MDSC）。自分泌和旁分泌STAT 3的激活在乳腺癌中的作用 癌细胞和肿瘤相关免疫细胞中的免疫调节因子增强淋巴瘤的致瘤性和致耐受性 潜力为了克服缺乏STAT 3的药理学抑制剂所带来的挑战，我们开发了一种 通过物理连接siRNA与TLR 9，将治疗性siRNA特异性递送到骨髓和B细胞中的策略 配体/激动剂，CpG寡脱氧核苷酸（ODN）。我们已经在多个肿瘤模型中证明， 使用CpG-STAT 3siRNA沉默STAT 3的局部肿瘤治疗，刺激全身抗肿瘤免疫， 除了诱导直接B细胞淋巴瘤肿瘤细胞凋亡和对放射治疗（RT）的敏感性之外。我们 建议将CpG-STAT 3siRNA转移到NHL的1b期临床试验中。在当前SPORE的第10年，我们 在该项目中包括第二代STAT 3抑制剂：将CpG连接到高亲和力的STAT 3-DNA结合 STAT 3诱饵ODN（dODN），其有效地竞争STAT 3 DNA结合。相比 CpG-STAT 3siRNA、CpG-STAT 3dODN表现出改善的核酸酶抗性，这允许系统性的 晚期播散性淋巴瘤的给药和治疗。我们预计随着临床试验的进行 第一个CpG-STAT 3siRNA策略与RT一起在局部环境中，并与新的优化， CpG-STAT 3dODN用于全身给药，所提出的研究将加速开发新的， 针对NHL细胞内STAT 3的有效和安全的基于核苷酸的免疫治疗策略， 潜在的其他血液恶性肿瘤。

PROJECT SUMMARY Non-Hodgkin lymphoma (NHL) is a heterogeneous group of diseases of mainly B-cell origin. NHL incidence is progressively increasing, making it the sixth most common cancer in the US, with over 70,000 estimated new cases in 2015. The NHLs range from indolent to aggressive cancer such as diffuse large B-cell lymphomas of activated B-cell-like type (ABC-DLBCL). Growing evidence links B cell lymphoma patients’ poor survival and immune suppression to persistent activation of signal transducer and activator of transcription 3 (STAT3). In ABC-DLBCL, genetic mutations augment Toll-like receptor 9 (TLR9)/MyD88 signaling, thereby leading to secretion of cytokines that induce STAT3 activation in lymphoma cells and in the tumor-associated immune cells, such as myeloid-derived suppressor cells (MDSCs). The autocrine and paracrine STAT3 activation in cancer cells and in the tumor-associated immune cells enhances lymphoma’s tumorigenic and tolerogenic potential. To overcome the challenge imposed by lack of pharmacological inhibitors of STAT3, we developed a strategy to deliver therapeutic siRNA specifically into myeloid and B cells, by physically linking siRNA to TLR9 ligands/agonists, CpG oligodeoxynucleotides (ODNs). We have demonstrated in multiple tumor models that local tumor treatment using CpG-STAT3siRNA silences STAT3, stimulating systemic antitumor immunity, in addition to inducing direct B-cell lymphoma tumor cell apoptosis and sensitivity to radiation therapy (RT). We propose to move CpG-STAT3siRNA to phase 1b clinical trials in NHL. In year 10 of the current SPORE, we included in the project a second generation STAT3 inhibitor: linking CpG to a high-affinity STAT3-DNA binding sequence called STAT3decoy ODN (dODN), which effectively competes STAT3 DNA binding. Compared to CpG-STAT3siRNA, CpG-STAT3dODN exhibits improved nuclease-resistance which allows for systemic administration and treatment of advanced, disseminated lymphomas. We anticipate that with the clinical testing of the first CpG-STAT3siRNA strategy together with RT in the local setting, and with the optimization of new CpG-STAT3dODN for systemic administration, the proposed studies will accelerate development of novel, effective and safe nucleotide-based immunotherapeutic strategies for targeting intracellular STAT3 in NHL and potentially other hematologic malignancies.