miR-155 targeted therapeutics for precision medicine in lung cancer

MiR-155是一种高度致癌的微小RNA(MiRNA)，它的解除调控与多种基因有关 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。 美国相关死亡与改善患者生存的令人沮丧的临床进展有关，这是由于 抗药性。我们已经证明miR-155在介导化疗耐药中发挥作用。 非小细胞肺癌。抗miR-155-DOPC治疗显著减少肿瘤生长并使NSCLC对 标准护理铂为基础的化疗药物，在活体原位小鼠模型中没有毒性。和平号- 155作用于TP53依赖的机制，触发导致化疗耐药的反馈回路。 肿瘤微环境(TME)在肿瘤的发生发展中起着重要作用，特别是通过 通过与癌细胞胞外转移高水平表达miR-155的单核/巨噬细胞。我们 开发了纳米脂质体结合适体来特异性靶向Axl受体，显著过度表达 除靶向miR-155外，还可由非小细胞肺癌肿瘤细胞和单核/巨噬细胞表达。通过 在纳米递送中用抗miR-155补充具有生命威胁毒性的标准干预 载体(如单脂纳米脂质体颗粒，SLNPs)，我们预计是安全无毒的，我们 期待我们的发现改变非小细胞肺癌的治疗方案。此MPI修订应用程序的主要目标是 进行临床前安全性和毒性研究，以测试抗miR-155佐剂的疗效和安全性 联合SLNP-抗miR-155或Ax1-APT-SLNP-抗miR-155，或联合 顺铂和长春瑞滨。这些临床前研究将为研究新药(IND)铺平道路 应用抗miR-155治疗非小细胞肺癌等化疗耐药肿瘤。我们 计划：1)通过在非小细胞肺癌中使用两种类型的SLNP来靶向癌细胞和TME中的miR-155；2) 基于生物相容纳米给药确定抗miR-155治疗的毒性 动物研究；3)确定可用于治疗的miR-155靶点的全谱 4)建立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，包括昼夜给药；5)确定体内抗肿瘤 肿瘤靶向双效Axl-APT-SLNP-anti-miR-155纳米药物单独及联合治疗的疗效 在原位和患者来源的异种移植模型中进行化疗，最后，6)为 Ind应用程序。我们提议的最终结果将是建立抗miR-155对 肿瘤内直接靶向miR-155和TME联合现有药物治疗非小细胞肺癌 化疗。我们预计抗miR-155将显著降低非小细胞肺癌的死亡率 任何主要的副作用，还可以提高总体存活率。这样的研究可以进一步扩大到有针对性的 治疗策略，如检查点抑制，如果这些成为护理的标准。

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.