Novel miRNA-based drug CD5-2 reduces liver tumor growth in diethylnitrosamine-treated mice by normalizing tumor vasculature and altering immune infiltrate.

Article

作者: Vadas, Mathew A ; Boland, Jade ; Zhao, Yang ; Kench, James ; McCaughan, Geoffrey W ; Chen, Jinbiao ; McKenzie, Catriona ; Ting, Ka Ka ; Lockwood, Glen ; Gamble, Jennifer R ; Liu, Ken

IntroductionLiver cancers exhibit abnormal (leaky) vasculature, hypoxia and an immunosuppressive microenvironment. Normalization of tumor vasculature is an emerging approach to treat many cancers. Blockmir CD5-2 is a novel oligonucleotide-based inhibitor of the miR-27a interaction with VE-Cadherin, the endothelial-specific cadherin. The combination of a vasoactive medication with inhibition of immune checkpoints such as programmed cell death protein 1 (PD1) has been shown to be effective in treating liver cancer in humans. We aimed to study the effect of CD5-2 combined with checkpoint inhibition (using an antibody against PD1) on liver tumor growth, vasculature and immune infiltrate in the diethylnitrosamine (DEN)-induced liver tumor mouse model.MethodsWe first analyzed human miR-27a and VE-Cadherin expression data from The Cancer Genome Atlas for hepatocellular carcinoma. CD5-2 and/or anti-PD1 antibody were given to the DEN-treated mice from age 7-months until harvest at age 9-months. Tumor and non-tumor liver tissues were analyzed using histology, immunohistochemistry, immunofluorescence and scanning electron microscopy.ResultsHuman data showed high miR-27a and low VE-Cadherin were both significantly associated with poorer prognosis. Mice treated with CD5-2 plus anti-PD1 antibody had significantly smaller liver tumors (50% reduction) compared to mice treated with either agent alone, controls, or untreated mice. There was no difference in tumor number. Histologically, tumors in CD5-2-treated mice had less leaky vessels with higher VE-Cadherin expression and less tumor hypoxia compared to non-CD5-2-treated mice. Only tumors in the combination CD5-2 plus anti-PD1 antibody group exhibited a more favorable immune infiltrate (significantly higher CD3+ and CD8+ T cells and lower Ly6G+ neutrophils) compared to tumors from other groups.DiscussionCD5-2 normalized tumor vasculature and reduced hypoxia in DEN-induced liver tumors. CD5-2 plus anti-PD1 antibody reduced liver tumor size possibly by altering the immune infiltrate to a more immunosupportive one.

2021-02-01·Gland Surgery4区 · 医学

The immune-related gene CD52 is a favorable biomarker for breast cancer prognosis

4区 · 医学

Article

作者: Fang, Dalang ; Zou, Caihua ; Chen, Yongcheng ; Huang, Qianfang ; Lu, Guan-Ming ; Lin, Jiayao ; Huang, Minyu ; Ma, Yan-Fei ; Luo, Zhizhai ; Qin, Qiang ; Meng, Dongdong ; Huang, Qun

BACKGROUNDAn increasing number of studies have demonstrated a role for the tumor microenvironment in tumorigenesis, disease progression, and therapeutic response. This present study aimed to screen the significant immune-related genes and their possible role in the prognosis of breast cancer (BRCA).METHODSThe transcriptome data and clinical data of breast cancer were collected from The Cancer Genome Atlas (TCGA), and the immune scores and stromal scores were calculated by ESTIMATE algorithm. The differentially expressed genes were screened base on immune and stromal scores (high score vs. low score), than the intersected genes were used for subsequent functional enrichment analysis and protein-protein interaction (PPI) analysis. Furthermore, the key gene was identified by the intersection of the hub genes of PPI network and the prognostic genes of breast cancer. Finally, we explored the infiltration of immune cells of BRCA base on the CIBERSORT algorithm, and analysis the relationship between key gene and immune cells.RESULTSHigh levels of CD52 expression were detected in the early stages of breast cancer and were associated with favorable prognosis. Overexpression of CD52 led to higher infiltrations of M1 macrophages, monocytes, T follicular helper cells, and resting memory CD4 T cells. Downregulation of CD52 resulted in high infiltrations of M2 macrophages. Therefore, high expression of CD52 may negatively regulate the infiltration of M2 macrophages but accelerate the infiltration of anti-cancer immune cells, and thus, high expression of CD52 may have a protective effect in breast cancer patients.CONCLUSIONSCD52 can increase the infiltration of anti-cancer immune cells but inhibit the infiltration of M2 macrophages, thereby improving the prognosis of breast cancer patients.

2019-02-01·Diabetologia1区 · 医学

Therapeutic regulation of VE-cadherin with a novel oligonucleotide drug for diabetic eye complications using retinopathy mouse models

1区 · 医学

Article

作者: Li, Jia ; Vadas, Mathew A ; Shen, Weiyong ; Gillies, Mark ; Coleman, Paul ; Moller, Thorleif ; Yam, Michelle ; Gamble, Jennifer R ; Ting, Ka Ka ; Chan-Ling, Tailoi ; Zhao, Yang

AIMS/HYPOTHESISA major feature of diabetic retinopathy is breakdown of the blood-retinal barrier, resulting in macular oedema. We have developed a novel oligonucleotide-based drug, CD5-2, that specifically increases expression of the key junctional protein involved in barrier integrity in endothelial cells, vascular-endothelial-specific cadherin (VE-cadherin). CD5-2 prevents the mRNA silencing by the pro-angiogenic microRNA, miR-27a. CD5-2 was evaluated in animal models of ocular neovascularisation and vascular leak to determine its potential efficacy for diabetic retinopathy.METHODSCD5-2 was tested in three mouse models of retinal dysfunction: conditional Müller cell depletion, streptozotocin-induced diabetes and oxygen-induced retinopathy. Vascular permeability in the Müller cell-knockout model was assessed by fluorescein angiography. The Evans Blue leakage method was used to determine vascular permeability in streptozotocin- and oxygen-induced retinopathy models. The effects of CD5-2 on retinal neovascularisation, inter-endothelial junctions and pericyte coverage in streptozotocin- and oxygen-induced retinopathy models were determined by staining for isolectin-B4, VE-cadherin and neural/glial antigen 2 (NG2). Blockmir CD5-2 localisation in diseased retina was determined using fluorescent in situ hybridisation. The effects of CD5-2 on VE-cadherin expression and in diabetic retinopathy-associated pathways, such as the transforming growth factor beta (TGF-β) and wingless/integrated (WNT) pathway, were confirmed using western blot of lysates from HUVECs, a mouse brain endothelial cell line and a VE-cadherin null mouse endothelial cell line.RESULTSCD5-2 penetrated the vasculature of the eye in the oxygen-induced retinopathy model. Treatment of diseased mice with CD5-2 resulted in reduced vascular leak in all three animal models, enhanced expression of VE-cadherin in the microvessels of the eye and improved pericyte coverage of the retinal vasculature in streptozotocin-induced diabetic models and oxygen-induced retinopathy models. Further, CD5-2 reduced the activation of retinal microglial cells in the streptozotocin-induced diabetic model. The positive effects of CD5-2 seen in vivo were further confirmed in vitro by increased protein expression of VE-cadherin, SMAD2/3 activity, and platelet-derived growth factor B (PDGF-B).CONCLUSIONS/INTERPRETATIONCD5-2 has therapeutic potential for individuals with vascular-leak-associated retinal diseases based on its ease of delivery and its ability to reverse vascular dysfunction and inflammatory aspects in three animal models of retinopathy.

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适应症	最高研发状态	国家/地区	公司	日期
血管疾病	临床3期	丹麦	Ranger Biotechnologies A/S	2012-09-16
血管疾病	临床3期	澳大利亚	Centenary Institute of Cancer Medicine and Cell Biology	2012-09-16
实体瘤	临床前	丹麦	Ranger Biotechnologies A/S	-