更新于：2024-11-01

LAMA4

更新于：2024-11-01

基本信息

别名

LAMA3、LAMA4、laminin subunit alpha 4

+ [4]

简介

Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.

关联

项与 LAMA4 相关的药物

AG-101

靶点

CD29 x EGFR x LAMA4

作用机制

CD29抑制剂 [+2]

在研机构

Arrogene, Inc.

原研机构

Cedars-Sinai Health System

在研适应症

乳腺癌 [+2]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

2A3 mAb (Northwestern University)

靶点

LAMA4

作用机制

LAMA4 inhibitors

在研机构

Northwestern University

原研机构

Northwestern University

在研适应症

病理性新生血管

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 LAMA4 相关的临床结果

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100 项与 LAMA4 相关的转化医学

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0 项与 LAMA4 相关的专利（医药）

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156

项与 LAMA4 相关的文献（医药）

2024-10-01·Cancer Medicine

New Anti‐Angiogenic Therapy for Glioblastoma With the Anti‐Depressant Sertraline

Article

作者: Fujimura, Atsushi ; Kurozumi, Kazuhiko ; Date, Isao ; Matsumoto, Yuji ; Michiue, Hiroyuki ; Tsuboi, Nobushige ; Suruga, Yasuki ; Otani, Yoshihiro ; Ishida, Joji ; Matsui, Hideki ; Fujii, Kentaro ; Uneda, Atsuhito

ABSTRACTBackground and AimsAnti‐angiogenic therapies prolong patient survival in some malignancies but not glioblastoma. We focused on the relationship between the differentiation of glioma stem like cells (GSCs) into tumor derived endothelial cells (TDECs) and, anti‐angiogenic therapy resistance. Especially we aimed to elucidate the mechanisms of drug resistance of TDECs to anti‐angiogenic inhibitors and identify novel anti‐angiogenic drugs with clinical applications.ResultsThe mouse GSCs, 005, were differentiated into TDECs under hypoxic conditions, and TDECs had endothelial cell characteristics independent of the vascular endothelial growth factor (VEGF) pathway. In vivo, inhibition of the VEGF pathway had no anti‐tumor effect and increased the percentage of TDECs in the 005 mouse model. Novel anti‐angiogenic drugs for glioblastoma were evaluated using a tube formation assay and a drug repositioning strategy with existing blood–brain barrier permeable drugs. Drug screening revealed that the antidepressant sertraline inhibited tube formation of TDECs. Sertraline was administered to differentiated TDECs in vitro and 005 mouse models in vivo to evaluate genetic changes by RNA‐Seq and tumor regression effects by immunohistochemistry and MRI. Sertraline reduced Lama4 and Ang2 expressions of TDEC, which play an important role in non‐VEGF‐mediated angiogenesis in tumors. The combination of a VEGF receptor inhibitor axitinib, and sertraline improved survival and reduced tumor growth in the 005 mouse model.ConclusionCollectively, our findings showed the diversity of tumor vascular endothelial cells across VEGF and non‐VEGF pathways led to anti‐angiogenic resistance. The combination of axitinib and sertraline can represent an effective anti‐angiogenic therapy for glioblastoma with safe, low cost, and fast availability.

2024-09-01·Recent Patents on Anti-Cancer Drug Discovery

Comprehensive Genomic Analysis of Puerarin in Inhibiting Bladder Urothelial Carcinoma Cell Proliferation and Migration

Article

作者: Liu, Ying ; Shi, Zhen-Duo ; Wang, Jing-kai ; Zhang, Ge-jin ; Liu, Peng-fei ; Hao, Lin ; Pang, Kun ; Xu, Hao ; Ding, Ji-cun ; Xu, Peng ; Pan, Deng ; Ma, Yu-yang ; Wang, Hai-luo

Background:Bladder urothelial carcinoma (BUC) ranks second in the incidence of urogenital system tumors, and the treatment of BUC needs to be improved. Puerarin, a traditional Chinese medicine (TCM), has been shown to have various effects such as anti-cancer effects, the promotion of angiogenesis, and anti-inflammation. This study investigates the effects of puerarin on BUC and its molecular mechanisms.Methods:Through GeneChip experiments, we obtained differentially expressed genes (DEGs) and analyzed these DEGs using the Ingenuity® Pathway Analysis (IPA®), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway enrichment analyses. The Cell Counting Kit 8 (CCK8) assay was used to verify the inhibitory effect of puerarin on the proliferation of BUC T24 cells. String combined with Cytoscape® was used to create the Protein-Protein Interaction (PPI) network, and the MCC algorithm in cytoHubba plugin was used to screen key genes. Gene Set Enrichment Analysis (GSEA®) was used to verify the correlation between key genes and cell proliferation.Results:A total of 1617 DEGs were obtained by GeneChip. Based on the DEGs, the IPA® and pathway enrichment analysis showed they were mainly enriched in cancer cell proliferation and migration. CCK8 experiments proved that puerarin inhibited the proliferation of BUC T24 cells, and its IC50 at 48 hours was 218μmol/L. Through PPI and related algorithms, 7 key genes were obtained: ITGA1, LAMA3, LAMB3, LAMA4, PAK2, DMD, and UTRN. GSEA showed that these key genes were highly correlated with BUC cell proliferation. Survival curves showed that ITGA1 upregulation was associated with poor prognosis of BUC patientsConclusion:Our findings support the potential antitumor activity of puerarin in BUC. To the best of our knowledge, bioinformatics investigation suggests that puerarin demonstrates anticancer mechanisms via the upregulation of ITGA1, LAMA3 and 4, LAMB3, PAK2, DMD, and UTRN, all of which are involved in the proliferation and migration of bladder urothelial cancer cells.

2024-08-02·Journal of Proteome Research

Extracellular Matrix Protein Signatures of the Outer and Inner Zones of the Rat Adrenal Cortex

Article

作者: Freitas, Danilo Henriques de Oliveira ; Lotfi, Claudimara Ferini Pacicco ; Auricino, Thais Barabba ; Kremer, Jean Lucas ; Palmisano, Giuseppe ; Bongiovani Rodrigues, Fernanda ; Santiago, Veronica Feijoli

This study analyzes the extracellular matrix (ECM) signatures of the outer (OF = capsule + subcapsular + zona glomerulosa cells) and inner fractions (IF = zona fasciculata cells) of the rat adrenal cortex, which comprise two distinct microenvironment niches. Proteomic profiles of decellularized OF and IF samples, male and female rats, identified 252 proteins, with 32 classified as ECM-component and ECM-related. Among these, 25 proteins were differentially regulated: 17 more abundant in OF, including Col1a1, Col1a2, Col6a1, Col6a2, Col6a3, Col12a1, Col14a1, Lama5, Lamb2, Lamc1, Eln, Emilin, Fbln5, Fbn1, Fbn2, Nid1, and Ltbp4, and eight more abundant in IF, including Col4a1, Col4a2, Lama2, Lama4, Lamb1, Fn1, Hspg2, and Ecm1. Eln, Tnc, and Nid2 were abundant in the female OF, while Lama2, Lama5, Lamb2, and Lamc1 were more abundant in the male IF. The complex protein signature of the OF suggests areas of tissue stress, stiffness, and regulatory proteins for growth factor signaling. The higher concentrations of Col4a1 and Col4a2 and their role in steroidogenesis should be further investigated in IF. These findings could significantly enhance our understanding of adrenal cortex functionality and its implications for human health and disease. Key findings were validated, and data are available in ProteomeXchange (PXD046828).

项与 LAMA4 相关的新闻（医药）

2022-12-15

·生物谷

Science子刊：揭开乳腺癌的脑转移通路，并提出潜在治疗策略

这项研究表明，连接蛋白（Cx）介导的FAK-NFκB信号通路是一种促进癌细胞在大脑中定植的关键分子机制。考虑到癌症患者脑转移性疾病的治疗选择十分有限，FAK抑制剂可能是目前最有希望的、治疗癌细胞脑转移癌症最令人困惑和最具毁灭性的特点之一是其潜在的致命“旅行癖”，即癌细胞从原发肿瘤扩散到新的、遥远的器官组织。这个过程被称为“转移”，从原发肿瘤中出发后，这些穷凶极恶的癌细胞搭乘血液或淋巴系统的便车，像蒲公英一般洒向身体的各个角落。值得注意的是，不少研究发现，不同类型的癌细胞具有不同组织器官的转移偏好。例如，脑转移在乳腺癌晚期患者中发病率增加，这是一种十分严重的并发症，脑转移患者往往身体素质和生活质量迅速下滑，治疗预后极其不佳。因此，临床上迫切需要开发有效的疗法来预防和治疗脑转移。近日，瑞士弗里堡大学的研究人员在 Science Translational Medicine 期刊发表了题为：Connexins orchestrate progression of breast cancer metastasis to the brain by promoting FAK activation 的研究论文。该研究表明，连接蛋白（Cx）和局部粘着斑激酶（FAK）在癌细胞的脑转移中起主要作用，FAK激活促进了癌细胞粘附、肿瘤-星形胶质细胞的相互作用和脑实质内的肿瘤存活。更重要的是，在乳腺癌脑转移模型中使用FAK抑制剂可以抑制脑转移的进展，表明靶向Cx-FAK信号通路可能有助于预防和治疗乳腺癌相关的脑转移疾病。在过去的30年里，科学家们在乳腺癌的治疗上取得了巨大的进步，各种联合治疗和免疫疗法的进展使得乳腺癌幸存者数量增加了好几倍，很大一部分患者在治疗后的预期寿命正常。然而，根据Breastcancer.org网站的数据，约30%被诊断为早期乳腺癌的女性最终发展为转移性疾病，而在这些转移性乳腺癌患者中，约10%-15%的四期患者有脑转移。其中，患有Her2阳性或三阴性乳腺癌等侵袭性更强的乳腺癌亚型患者发生脑转移的风险更高。器官定植是癌细胞转移的主要限速步骤，因此，靶向器官定植，而不是肿瘤细胞扩散和归巢到远处器官，是一种极具吸引力的治疗方法。事实上，许多癌症患者在原发性肿瘤诊断之前癌细胞就已经发生扩散了。在这项最新研究中，研究团队报道了一种、独特的、自发的强大的自发性乳腺癌脑转移临床前模型——4T1-BM2，该模型有助于揭示引导脑转移扩散和定位点的分子机制。研究人员在由此衍生的小鼠D2A1-BM2模型和人MDA231-BrM2模型中进行了实验验证。基于4T1-BM2构建乳腺癌自发性脑转移小鼠模型研究团队首先通过基因表达分析和功能研究，以及加上临床转录组学和组织病理学调查，确定连接蛋白（Cx）和局部粘着斑激酶（FAK）是组织乳腺癌在大脑定植的关键枢纽。其中，Cx31促进同型肿瘤细胞粘附、异型肿瘤-星形胶质细胞相互作用和FAK磷酸化，FAK信号促进NF-κB激活，诱导Lamc2表达和层粘连蛋白5沉积，α6整合素介导的粘附，并在脑实质内持续生存和生长。与之相对应，在人MDA231-BrM2模型中，该过程涉及人类同源分子CX43、LAMA4和α3整合素。 Cx31诱导FAK依赖的NF-κB激活，促使4T1-BM2和MDA231- BrM2细胞在大脑中存活更关键的是，当研究人员使用FAK抑制剂对乳腺癌小鼠模型进行全身性治疗时，癌细胞脑转移得到了明显缓解。事实上，这种药物已经在人体临床试验中进行了测试，它抑制了转移性乳腺癌细胞在大脑中的生长。 FAK信号通路是脑转移进展所必需的总而言之，这项研究表明，连接蛋白（Cx）介导的FAK-NFκB信号通路是一种促进癌细胞在大脑中定植的关键分子机制。考虑到癌症患者脑转移性疾病的治疗选择十分有限，FAK抑制剂可能是目前最有希望的、治疗癌细胞脑转移患者的治疗候选药物。