miR-155 targeted therapeutics for precision medicine in lung cancer

miR-155是一种高度致癌的microRNA（miRNA），其失调与多种肿瘤相关。 包括肺癌在内的恶性肿瘤。非小细胞肺癌（NSCLC）是导致癌症的主要原因- 在美国，相关死亡与令人沮丧的临床进展，以改善患者的生存，由于发展， 耐药性我们已经证明，miR-155在介导化疗耐药中发挥作用， NSCLC。用抗miR-155-DOPC治疗显著降低肿瘤生长并使NSCLC对miR-155-DOPC再敏感。 在体内原位小鼠模型中没有毒性的护理标准铂基化疗剂。miR- 155作用于TP 53依赖性机制，触发导致化疗抗性的反馈回路。 肿瘤微环境（TME）在促进癌症的发生中起着重要作用，特别是通过 通过与癌细胞的外泌体转移表达高水平miR-155的单核细胞/巨噬细胞。我们 开发了纳米脂质体结合的适体，以特异性靶向AXL受体， 除了靶向miR-155外，NSCLC肿瘤细胞也表达miR-155，单核细胞/巨噬细胞也表达miR-155。通过 在纳米递送中用抗miR-155补充具有危及生命的毒性的标准干预措施 载体（如单脂质纳米脂质体颗粒，SLNP），我们预计是安全和无毒的，我们 希望我们的发现能改变NSCLC的治疗方案。此MPI修订版应用程序的主要目标是 进行临床前安全性和毒性研究，以测试佐剂抗miR-155的有效性和安全性 与SLNP-抗-miR-155或AXL-Apt-SLNP-抗-miR-155偶联的单独或与 顺铂和长春瑞滨。这些临床前研究将为研究性新药（IND）铺平道路 本申请涉及抗miR-155治疗在NSCLC和其他化疗抗性肿瘤中的应用。我们 计划：1）通过在NSCLC中使用两种类型的SLNP在癌细胞和TME中靶向miR-155; 2） 基于使用生物相容性纳米递送的递送，确定抗miR-155疗法的毒性， 动物研究; 3）确定可用于治疗开发和使用的miR-155靶标的全谱 4）开发新的数学模型来确定抗miR-155的治疗价值 治疗，基于多个参数，包括昼夜节律给药; 5）确定体内抗肿瘤药物 肿瘤靶向双效AXL-Apt-SLNP-抗miR-155纳米治疗剂单独和组合的功效 在原位和患者来源的异种移植物模型中进行化疗，最后，6）将结果汇编为 IND申请。我们建议的最终结果将是确定抗miR-155的功效， 通过直接靶向肿瘤和TME中的miR-155与现有的 化疗我们预计抗miR-155可以显着降低非小细胞肺癌的死亡率，而不会 任何主要的副作用，并提高总生存率。这些研究可以进一步扩大， 治疗策略，如检查点抑制，如果这些成为护理标准。

The deregulation of miR-155, a highly oncogenic microRNA (miRNA), has been associated with a wide variety of malignancies including lung cancer. Non-small-cell lung cancer (NSCLC) is the leading cause of cancer- related death in the US with dismal clinical advances to improve patient’s survival, due to the development of drug-resistance. We have demonstrated that miR-155 plays a role in mediating resistance to chemotherapy in NSCLC. Treatment with anti-miR-155-DOPC significantly reduced tumor growth and resensitized NSCLC to standard of care platinum-based chemotherapeutics with no toxicity in an in vivo orthotopic mouse model. miR- 155 acts on a TP53-dependent mechanism, triggering a feedback loop leading to chemotherapy resistance. Tumor microenvironment (TME) plays an important role in the promotion of cancer, specifically via monocyte/macrophage cells that express high levels of miR-155 by exosomal transfer with cancer cells. We developed nanoliposomal-bound aptamers to specifically target the AXL receptor, significantly overexpressed by NSCLC tumor cells and expressed also by monocyte/macrophage cells, in addition to targeting miR-155. By complementing standard interventions that have life-threatening toxicities with anti-miR-155 in nanodelivery vehicles (like single-lipid nanoliposomal particles, SLNPs), which we anticipate to be safe and non-toxic, we expect our findings to change treatment regimens for NSCLC. The main goal of this MPI revised application is to perform preclinical safety and toxicity studies to test the efficacy and safety of adjuvant anti-miR-155 therapies, coupled with SLNP-anti-miR-155 or AXL-Apt-SLNP-anti-miR-155, alone or in combination with cisplatin and vinorelbin. These preclinical studies will pave the way to an Investigational New Drug (IND) application for the use of anti-miR-155 treatment in NSCLC, and other chemotherapeutic resistant tumors. We plan to: 1) target miR-155 both in cancer cells and in TME by using the two types of SLNPs in NSCLC; 2) determine the toxicity of anti-miR-155 therapies based on the delivery using biocompatible nanodelivery in animal studies; 3) identify the full spectrum of miR-155 targets that could be therapeutically exploited and used for reducing toxicity; 4) develop novel mathematical models to determine the therapeutic value of anti-miR-155 treatment, based on multiple parameters, including circadian administration; 5) determine the in vivo antitumor efficacy of tumor targeted dual-effect AXL-Apt-SLNP-anti-miR-155 nanotherapeutics alone and in combination with chemotherapy in orthotopic and patient-derived xenograft models and, finally, 6) to compile the results for the IND application. The final outcome of our proposal would be to establish the efficacy of anti-miR-155 to treat NSCLC by directly targeting miR-155 in the tumor and TME in combination with existing chemotherapeutic treatments. We expect anti-miR-155 to significantly reduce the mortality of NSCLC without any major side effects, and also improve overall survival. Such studies can be further expanded for targeted therapeutic strategies, such as checkpoint inhibition, if these become the standard of care.