miR-155 targeted therapeutics for precision medicine in lung cancer

miR-155靶向治疗用于肺癌精准医疗

基本信息

批准号：
10460112
负责人：
George A Calin
金额：
$ 50.2万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-03 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460112
关键词：
3-Dimensional Adjuvant Adverse reactions Animals Biology Cancer Etiology Cancer cell line Cells Cessation of life Chemoresistance Chemosensitization Chemotherapy-Oncologic Procedure Cisplatin Clinical Clinical Trials Code Complement Coupled Data Development Dose Drug Delivery Systems Drug Kinetics Drug or chemical Tissue Distribution Drug resistance Drug usage Failure Feedback Genes Goals Hybrids In Vitro Intervention Investigational New Drug Application Life Link Lipids Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating MicroRNAs Modeling Molecular Mutate Nano delivery Non-Small-Cell Lung Carcinoma Normal Cell Oncogenic Organ Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Platinum Play Probability Prognosis Proteins Regimen Resistance Resistance development Role Safety Specificity System TP53 gene Testing Therapeutic Therapeutic Effect Tissues Toxic effect Treatment Protocols Tumor Cell Invasion Tumor Suppressor Proteins Tumor-associated macrophages Untranslated RNA Vinorelbine Woman angiogenesis appropriate dose aptamer axl receptor tyrosine kinase base biomaterial compatibility cancer cell cancer therapy checkpoint inhibition chemosensitizing agent chemotherapeutic agent chemotherapy circadian clinical translation deep sequencing drug development efficacy evaluation efficacy testing exosome improved in vivo innovation macrophage mathematical model men monocyte mortality mouse model multi-scale modeling nanoliposome nanoparticle nanotherapeutic neoplastic cell novel overexpression particle patient derived xenograft model precision medicine preclinical safety preclinical study preclinical toxicity receptor relapse patients side effect standard of care targeted treatment therapeutic miRNA therapeutic target tumor tumor growth tumor microenvironment uptake

项目摘要

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.

miR-155（一种高度致癌的 microRNA (miRNA)）的失调与多种疾病有关。包括肺癌在内的恶性肿瘤是导致癌症的主要原因。在美国，由于改善患者生存率的临床进展惨淡，导致相关死亡我们已经证明 miR-155 在介导化疗耐药中发挥作用。 NSCLC。抗 miR-155-DOPC 治疗显着减少肿瘤生长并使 NSCLC 对肿瘤重新敏感。护理标准铂类化疗药物在体内原位小鼠模型中无毒性。 155 作用于 TP53 依赖性机制，触发导致化疗耐药的反馈循环。肿瘤微环境（TME）在促进癌症发生方面发挥着重要作用，特别是通过通过与癌细胞进行外泌体转移来表达高水平 miR-155 的单核细胞/巨噬细胞。开发了纳米脂质体结合的适体，专门针对显着过度表达的 AXL 受体除了靶向 miR-155 外，还由 NSCLC 肿瘤细胞表达，也由单核细胞/巨噬细胞表达。在纳米递送中用抗 miR-155 补充具有危及生命毒性的标准干预措施载体（如单脂质纳米脂质体颗粒，SLNP），我们预计其是安全无毒的，我们期望我们的发现能够改变 NSCLC 的治疗方案本 MPI 修订申请的主要目标是。进行临床前安全性和毒性研究，以测试佐剂抗 miR-155 的功效和安全性疗法，与 SLNP-抗-miR-155 或 AXL-Apt-SLNP-抗-miR-155 联用，单独或组合这些临床前研究将为研究性新药 (IND) 铺平道路。抗 miR-155 治疗 NSCLC 和其他化疗耐药肿瘤的申请。计划：1) 通过在 NSCLC 中使用两种类型的 SLNP 来靶向癌细胞和 TME 中的 miR-155；基于使用生物相容性纳米递送的递送来确定抗 miR-155 疗法的毒性动物研究；3) 确定可用于治疗性开发和使用的全谱 miR-155 靶点降低毒性；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)确定体内抗肿瘤作用；肿瘤靶向双效 AXL-Apt-SLNP-抗 miR-155 纳米疗法单独和组合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) 汇总结果我们提案的最终结果是确定抗 miR-155 的功效。通过直接靶向肿瘤和 TME 中的 miR-155 并结合现有技术来治疗 NSCLC 我们预计抗 miR-155 药物可以显着降低 NSCLC 的死亡率，而无需进行化疗。任何主要的副作用，并且还可以提高总体生存率，这样的研究可以进一步扩大以进行有针对性的研究。治疗策略，例如检查点抑制，如果这些成为护理标准。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

How Does a Tumor Get Its Shape? MicroRNAs Act as Morphogens at the Cancer Invasion Front.

肿瘤是如何形成形状的？

DOI：
10.3390/ncrna6020023
发表时间：
2020
期刊：
Non-coding RNA
影响因子：
4.3
作者：
Vasilescu,Catalin;Tanase,Mihai;Giza,Dana;Procopiuc,Livia;Dragomir,MihneaP;Calin,AndGeorgeA
通讯作者：
Calin,AndGeorgeA

Competing Engagement of β-arrestin Isoforms Balances IGF1R/p53 Signaling and Controls Melanoma Cell Chemotherapeutic Responsiveness.

β-抑制蛋白亚型的竞争性参与平衡 IGF1R/p53 信号传导并控制黑色素瘤细胞化疗反应。

DOI：
10.1158/1541-7786.mcr-22-0871
发表时间：
2023
期刊：
Molecular cancer research : MCR
影响因子：
0
作者：
Cismas,Sonia;Pasca,Sylvya;Crudden,Caitrin;TrocoliDrakensjo,Iara;Suleymanova,Naida;Zhang,Simin;Gebhard,Benjamin;Song,Dawei;Neo,Shiyong;Shibano,Takashi;Smith,TerryJ;Calin,GeorgeA;Girnita,Ada;Girnita,Leonard
通讯作者：
Girnita,Leonard