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

项目总结 非霍奇金淋巴瘤(NHL)是一组以B细胞为主的异质性疾病。非霍奇金淋巴瘤发病率为 逐渐增加，使其成为美国第六大最常见的癌症，估计有超过7万名新发癌症 2015年的案件。NHL的范围从惰性癌症到侵袭性癌症，如弥漫性大B细胞淋巴瘤 活化的B细胞样型(ABC-DLBCL)。越来越多的证据表明B细胞淋巴瘤患者的低存活率和 对信号转导和转录激活子3(STAT3)持续激活的免疫抑制。在……里面 ABC-DLBCL，基因突变增强Toll样受体9(TLR9)/MyD88信号，从而导致 诱导淋巴瘤细胞和肿瘤相关免疫中STAT3激活的细胞因子的分泌 细胞，如髓系来源的抑制细胞(MDSCs)。大鼠自分泌和旁分泌STAT3的激活 癌细胞和肿瘤相关免疫细胞增强淋巴瘤的致瘤性和耐受性 潜力。为了克服缺乏STAT3的药物抑制剂所带来的挑战，我们开发了一种 通过将siRNA物理连接到TLR9，将治疗性siRNA特异性地输送到髓系和B细胞的策略 配体/激动剂，CpG寡核苷酸(ODN)。我们已经在多种肿瘤模型中证明了 使用CpG-STAT3siRNA局部治疗肿瘤可沉默STAT3，刺激全身抗肿瘤免疫 除了直接诱导B细胞淋巴瘤肿瘤细胞凋亡和对放射治疗(RT)的敏感性外。我们 建议将CpG-STAT3siRNA转移到NHL的1b期临床试验。在当前孢子的第10年，我们 该项目包括第二代STAT3抑制剂：将CpG与高亲和力的STAT3-DNA结合 序列称为STAT3诱骗ODN(DODN)，它有效地竞争STAT3 DNA结合。与.相比 CpG-STAT3siRNA、CpG-STAT3dODN表现出更好的核酸酶抗性，从而允许系统性 晚期播散性淋巴瘤的管理和治疗。我们期望通过临床测试实现这一点 在局部环境中与RT一起使用第一个CpG-STAT3siRNA策略，并与新的 CPG-STAT3dODN用于系统给药，所提出的研究将促进新的， 针对非霍奇金淋巴瘤和非霍奇金淋巴瘤细胞内STAT3的有效和安全的核苷酸免疫治疗策略 可能是其他恶性血液病。

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.