miR-155 targeted therapeutics for precision medicine in lung cancer

miR-155靶向治疗用于肺癌精准医疗

• 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
• 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

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是一种高度致癌的microRNA (miRNA)，其失调与多种疾病有关

项目成果

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
• 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