A Randomized, Open, Parallel-controlled, Multi-center , Phase Ib/Ⅱ Clinical Trial of YL-13027 and/or HY-0102 Combined With AG（Nab-paclitaxel and Gemcitabine) Regimen Chemotherapy for Metastatic Pancreatic Cancer

In Phase 1b study, six subjects will be enrolled in Arm A (YL-13027 + AG regimen) and Arm B (HY-0102 + AG regimen). The first 12 subjects will be evaluated for safety after one cycle. After safety assessment, subjects will start to enroll in Arm C (YL-13027 + HY-0102 + AG regimen). Each group is planned to include 12-20 subjects. According to the safety and efficacy results of 3 arms of subjects in phase Ib, 1-2 groups were selected for expansion, and a randomized controlled study will be conducted with the standard treatment AG （Arm 4）regimen chemotherapy.

开始日期2024-11-30

申办/合作机构

上海璎黎药业有限公司

100 项与 ALK5 x TGF-β 相关的临床结果

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100 项与 ALK5 x TGF-β 相关的转化医学

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0 项与 ALK5 x TGF-β 相关的专利（医药）

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项与 ALK5 x TGF-β 相关的文献（医药）

2025-01-01·Journal of Pharmaceutical and Biomedical Analysis

A study of the association of vitamin D receptor (VDR) as a predictive biomarker for immune checkpoint inhibitor therapy with immune invasion in colon adenocarcinoma

Article

作者: Lin, Ailing ; Chao, Guanqun ; Bao, Yang

Colon adenocarcinoma(COAD) is a primary and aggressive malignancy with the fifth highest mortality rate among cancers, and it is important to discover new strategies. The online database was used to analyze the correlation between Vitamin D receptor (VDR) and COAD, and further explore the immune infiltration and related gene networks.The expression and methylation levels of VDR was analyzed by using Timer database, GEPIA platform and UALCAN database. GeneMANIA database was used to analyze and obtain gene networks that are closely linked to VDR. UALCAN database was used to score the gene effects of VDR in colorectal cancer cell lines. The cBioPortal database was used for the detection of gene mutations. The survival curve analysis was carried out using the GEPIA database. The relationship between VDR expression and immune cell infiltration was analyzed by using the timer database and TISIDB database. TISIDB database was used to obtain VDR-related drug targets.The expression of VDR was significantly lower in COAD(p<0.05). The methylation level of VDR was significantly higher in COAD (p<0.05). The gene mutation rate of VDR in COAD was 2 %. OS and DFS were not associated with changes in the VDR gene in patients with COAD. VDR expression was correlated with CD4+T cell infiltration, macrophage infiltration, neutrophil infiltration, and dendritic cell infiltration. VDR has a clear correlation with ADORA2A, BTLA, CD160, CD244, CD274, CD96, CSF1R, CTLA4, HAVCR2, IL10, IDO1, LAG3, LGALS9, PDCD1, PDCD1LG2, PVRL2, TGFB1, TGFBR1, TIGIT and VTCN1.The expression of VDR is associated with immune infiltration in patients with COAD. VDR may be a new candidate biomarker for determining the level of immune infiltration and predicting immune checkpoint inhibitor therapy.

2024-12-01·Molecular Biology Reports

Caloric and time restriction diets improve acute kidney injury in experimental menopausal rats: role of silent information regulator 2 homolog 1 and transforming growth factor beta 1

Article

作者: Raji-Amirhasani, Alireza ; Bashiri, Hamideh ; Alavi, Samaneh Sadat ; Hajializadeh, Zahra ; Darvishzadeh Mahani, Fatemeh ; Khaksari, Mohammad ; Mousavi, Maryam Sadat

BACKGROUNDEstrogen has a protective impact on acute kidney injury (AKI); moreover, reducing the daily intake of calories impedes developing diseases. The present study aimed to determine the effects of calorie restriction (CR) and time restriction (TR) diets on the expression of silent information regulator 2 homolog 1 (SIRT1), transforming growth factor beta 1 (TGF-β1), and other indicators in the presence and absence of ovaries in AKI female rats.METHODSThe female rats were divided into two groups, ovariectomized (OVX) and sham, and were placed on CR and TR diets for eight weeks; afterward, AKI was induced by injecting glycerol, and kidney injury indicators and biochemical parameters were measured before and after AKI.RESULTSAfter AKI, the levels of urine albumin excretion rate, urea, and creatinine in serum, and TGF-β1 increased, while creatinine clearance and SIRT1 decreased in kidney tissue. CR improved kidney indicators and caused a reduction in TGF-β1 and an increase in SIRT1 in ovary-intact rats. Moreover, CR prevented total antioxidant capacity (TAC) decrease and malondialdehyde (MDA) increase resulting from AKI. Before AKI, an increase in body weight, fasting blood sugar (FBS), low-density lipoprotein (LDL), triglyceride (TG), and total cholesterol (TC), and a decrease in high-density lipoprotein (HDL) were observed in OVX rats compared to sham rats, but CR prevented these changes. The effects of TR were similar to those of CR in all indicators except for TGF-β1, SIRT1, urea, creatinine, and albumin.CONCLUSIONThe present study indicated that CR is more effective than TR in preventing AKI, probably by increasing SIRT1 and decreasing TGF-β1 in ovary-intact animals.

2024-12-01·Cellular and Molecular Life Sciences

NOR1 promotes the osteoblastic differentiation of human periodontal ligament stem cells via TGF-β signaling pathway

Article

作者: Li, Yicun ; Li, Mengqing ; Jing, Huan ; Ma, Guixing ; Yang, Hongyu ; Cao, Huiling ; Zheng, Yating ; Lin, Yuntao ; Wu, Yun

AbstractAlveolar bone loss is a main manifestation of periodontitis. Human periodontal ligament stem cells (PDLSCs) are considered as optimal seed cells for alveolar bone regeneration due to its mesenchymal stem cell like properties. Osteogenic potential is the premise for PDLSCs to repair alveolar bone loss. However, the mechanism regulating osteogenic differentiation of PDLSCs remain elusive. In this study, we identified Neuron-derived orphan receptor 1 (NOR1), was particularly expressed in PDL tissue in vivo and gradually increased during osteogenic differentiation of PDLSCs in vitro. Knockdown of NOR1 in hPDLSCs inhibited their osteogenic potential while NOR1 overexpression reversed this effect. In order to elucidate the downstream regulatory network of NOR1, RNA-sequencing was used. We found that downregulated genes were mainly enriched in TGF-β, Hippo, Wnt signaling pathway. Further, by western blot analysis, we verified that the expression level of phosphorylated-SMAD2/3 and phosphorylated-SMAD4 were all decreased after NOR1 knockdown. Additionally, ChIP-qPCR and dual luciferase reporter assay indicated that NOR1 could bind to the promoter of TGFBR1 and regulate its activity. Moreover, overexpression of TGFBR1 in PDLSCs could rescue the damaged osteogenic potential after NOR1 knockdown. Taken together, our results demonstrated that NOR1 could activate TGF-β/SMAD signaling pathway and positively regulates the commitment of osteoblast lineages of PDLSCs by targeting TGFBR1 directly.

项与 ALK5 x TGF-β 相关的新闻（医药）

2024-10-08

·今日头条

显著抑制肝癌转移！华中科技大学黄文杰团队：发现靶向肝癌转移的新策略

【导读】肝细胞癌(HCC)的转移严重威胁着患者的生存。GPR56在恶性肿瘤研究中受到广泛关注，在细胞表面信号传递中起着至关重要的作用。然而，其在HCC中的确切功能仍不明确。近日，华中科技大学黄文杰研究团队在期刊《Cell Death&Disease》上发表了研究论文，题为“GPR56 facilitates hepatocellular carcinoma metastasis by promoting the TGF-β signaling pathway”，本研究揭示了GPR56在人类肝癌病例中的表达水平显著升高，且升高的GPR56水平与不良预后相关。GPR56通过与TGFBR1相互作用调控TGF-β通路，从而促进HCC转移。同时，GPR56受TGF-β信号的典型级联调节，从而建立正反馈回路。此外，联合应用TGFBR1抑制剂GAL和GPR56抑制剂DHM显著抑制肝癌转移。靶向该信号通路的干预有望有效阻止GPR56介导的肝癌转移。 https://www.nature.com/articles/s41419-024-07095-6#Sec25 背景介绍 01 HCC是一种常见的恶性肿瘤，在全球癌症相关死亡中排名第三。由于在疾病晚期发现延迟、肿瘤频繁转移和手术切除后肿瘤复发，死亡率升高。尽管近几十年来取得了显著进展，但晚期HCC患者的预后仍然不理想。因此，了解控制HCC发展和转移的复杂分子机制至关重要。 TGF-β通路在肝脏疾病和肝细胞癌(HCC)中发挥多重作用，既促进肝纤维化和炎症，又抑制肿瘤增殖和促进转移。TGF-β蛋白与受体激酶结合，启动磷酸化依赖的信号级联反应，主要包括SMAD蛋白的下游信号。在癌症进展晚期，TGF-β通过刺激肿瘤细胞发生上皮-间充质转化(epithelial-mesenchymal transformation, EMT)促进肿瘤转移，发挥促癌作用。研究人员前期深入研究了TGF-β1/SMAD3经典信号机制，阐明了下游分子PTPRε和JunBP在促进肝癌迁移和转移中的作用。 GPR56在体内外均可促进肝癌的转移 02 为了研究GPR56对HCC的生物学效应，研究人员使用慢病毒在低表达水平的Hep3B细胞中稳定过表达GPR56，使用3种不同的shRNA在高表达水平的MHCC97H和HLF细胞中稳定敲低GPR56，选择shRNA-2进行了进一步实验。通过划痕实验和迁移实验，研究人员发现GPR56过表达增强了Hep3B细胞的迁移和侵袭能力，而在MHCC97H和HLF细胞中，GPR56敲低减弱了这些能力。这些结果共同证实了GPR56促进肝癌的迁移和侵袭。此外，通过蛋白质免疫印迹实验检测了EMT标志物，研究人员发现在肝癌细胞中上调GPR56促进波形蛋白和闭合蛋白的表达，同时抑制E-钙粘蛋白的表达，表明GPR56具有促进肝癌细胞EMT的能力。此外，研究人员还使用了一种小分子抑制剂DHM，它可以特异性地靶向GPR56，抑制其功能活性。在MHCC97H和Hep3B细胞中使用DHM后，划痕实验和迁移实验表明DHM显著降低肝癌细胞的迁移和侵袭能力。 GPR56在体内外均可促进肝癌的转移研究人员进一步验证了GPR56在体内的致癌功能。研究人员建立了裸鼠尾静脉肺转移瘤模型和原位肝移植瘤模型。尾静脉肺转移实验显示，与SH-CON组相比，SH-GPR56组荧光强度和肺种植体数量明显减少。与LV-CON组相比，OE-GPR56组荧光强度和肺内种植体数量均升高。与SH-CON组相比，SH-GPR56组原位肝转移模型荧光强度明显降低，肿瘤数量明显减少，生存时间明显延长，肺转移明显减少。OE-GPR56组与LV-CON组相比，荧光强度更高，肿瘤数量更多，肺转移结节增多，生存时间更短。基于这些结果，研究人员得出结论，GPR56促进肝癌的进展和促进转移。 GPR56通过TGFBR1促进肝癌转移 03 研究人员进一步研究了TGFBR1在GPR56促进肝癌细胞转移中的作用。在Hep3B LV-GPR56细胞中，敲低TGFBR1可降低p-SMAD3的表达。同样，在荧光素酶报告基因检测中，研究人员发现TGFBR1的敲低抑制了GPR56过表达引起的SBE荧光素酶活性的增加。通过划痕实验和迁移实验，研究人员发现TGFBR1的敲低消除了GPR56对细胞迁移和侵袭的促进作用。在过表达GPR56的Hep3B细胞中，研究人员使用小分子抑制剂SB431542抑制TGFBR1的磷酸化。研究人员观察到，当TGFBR1磷酸化被抑制时，肝癌细胞的迁移和侵袭能力同样被抑制。这些发现表明GPR56对TGF-β信号通路的调节依赖于TGFBR1。此外，研究人员构建了在GPR56敲低背景下过表达TGFBR1-WT和TGFBR1-S165D的MHCC97H细胞。研究人员发现，当TGFBR1的第165位氨基酸发生突变时，肝癌细胞中的TGF-β通路受到抑制，其迁移和侵袭能力降低。研究人员通过蛋白质免疫印迹实验检测EMT标志物时发现，在肝癌细胞中重建TGFBR1增强了波形蛋白和闭合蛋白的表达，而抑制了E-钙粘蛋白的表达，表明GPR56通过TGFBR1调控肝癌细胞的EMT。裸鼠原位移植实验显示，Hep3B-LV-GPR56组中TGFBR1表达下调后，肝脏肿瘤负荷降低，肺转移结节减少，生存时间延长。相反，在MHCC97H-SH-GPR56组中过表达TGFBR1-WT促进肿瘤生长和转移，而过表达TGFBR1-S165D无明显的促癌作用。研究表明TGFBR1参与了GPR56介导的肝癌转移。研究发现 04 本研究中，研究人员观察到GAL对高表达GPR56的HCC没有表现出显著的疗效。结合GAL的作用机制，研究人员推测这可能与GPR56诱导的TGFBR1激活有关，表明GPR56和GAL之间存在潜在的竞争相互作用。因此，研究人员使用小分子抑制剂DHM选择性地靶向GPR56。动物实验中，在GPR56高表达的HCC中，DHM和GAL联合治疗确实显示出比单药治疗更好的疗效，显著抑制HCC的转移。这些发现揭示了一种靶向GPR56诱导的HCC转移的新策略。【参考资料】 https://www.nature.com/articles/s41419-024-07095-6#Sec25 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会点击对应文字查看详情

临床研究临床终止

2024-10-06

·PipelineReview

TiumBio Announces First Patient Dosed in Phase 2 Clinical Trial of Oral Immuno-Oncology Drug TU2218

BOSTON, MA, USA and SEONGNAM, South Korea I October 4, 2024 I TiumBio Co., Ltd. (Kosdaq: 321550), a clinical-stage biopharmaceutical company focused on discovering and developing innovative therapeutics for patients with rare and incurable diseases, announced today that the first patient has been dosed in its Phase 2 clinical trial of TU2218. TU2218 is a novel oral dual inhibitor targeting TGFR1 and VEGFR2. TGF-ß and VEGF pathways are known to suppress the activity of immune checkpoint inhibitors (ICIs), so TU2218 is expected to improve the efficacy of ICIs by blocking the two pathways. In Phase 1a and 1b clinical trials, TiumBio evaluated the safety, pharmacokinetics, and pharmacodynamics of TU2218 as a monotherapy and in combination with Keytruda (pembrolizumab) in 41 patients with advanced solid tumors. These profiles were used to determine the dose levels for Phase 2 trials. The Phase 2a trial is designed to assess the safety and efficacy of TU2218 in combination with Keytruda in patients with head and neck squamous cell carcinoma (HNSCC), biliary tract cancer (BTC), and colorectal cancer (CRC). The Phase 2 trial begins at Seoul National University Hospital and Asan Medical Center in South Korea, which is planned to expand to hospitals in the United States. The first dose was administered to an HNSCC patient. HNSCC refers to malignant tumors that occur in the oral cavity, throat, larynx, or salivary glands. The standard treatment typically involves surgery and radiation therapy. According to Global Data, as of 2023, the number of HNSCC patients worldwide is estimated to be around 610,000, and it is expected to exceed 670,000 by 2030. “HNSCC is a disease with a high unmet medical need, as the average survival rate for first-line treatments is known to be only about one year,” said Hun-taek Kim, Ph.D., MBA, CEO of TiumBio. “We have selected cancer types for the Phase 2 clinical trial based on other trials that demonstrated strong anti-cancer effects from targeting TGF- ß or VEGF pathways. Our goal is to develop TU2218 as a first-line treatment for HNSCC,” he added. In the Phase 1b trial, among 10 patients with advanced solid tumors who received a 195mg daily dose (the determined dose for Phase 2) of TU2218 with Keytruda, three patients achieved partial response (PR) and five patients had stable disease (SD), yielding an 80% disease control rate (DCR). About TiumBio Co., Ltd. TiumBio (Kosdaq: 321550) is a clinical-stage biopharmaceutical company focused on the discovery and development of innovative therapeutics for patients with rare and incurable diseases. Its mission is to expand the hope and happiness of mankind through our science. TiumBio boasts three leading pipeline assets: merigolix (code name: TU2670), TU2218, and TU7710, all in various stages of clinical development. Merigolix is a once-daily, oral GnRH receptor antagonist being developed for the treatment of endometriosis and uterine fibroids and is undergoing in global Phase 2 clinical trials. TU2218 is a first-in-class oral immune-oncology therapy targeting TGF-β and VEGF pathways to promote response rates in cancer patients when used in combination with immune checkpoint inhibitors. TU7710 is a novel rFVIIa designed to extend its half-life in order to provide more clinical benefits to hemophilia patients with inhibitors. With its expertise in drug development, TiumBio is committed to the discovery and development of innovative treatments to ease the burden of debilitating diseases. For further information, visit our website at www.tiumbio.com/en and connect with us on LinkedIn . Contacts: Junseok Jang, Head of Corporate Communications & Investor Relations junseokjang@tiumbio.com Suna Cho, Manager, Corporate Communications & Investor Relations sunacho@tiumbio.com Da-ye Song, Manager, Corporate Communications & Investor Relations dayesong@tiumbio.com SOURCE: TiumBio

临床2期免疫疗法临床1期临床结果

2024-10-04

·PRNewswire

TiumBio Announces First Patient Dosed in Phase 2 Clinical Trial of Oral Immuno-Oncology Drug TU2218

TU2218 is a potentially first-in-class dual inhibitor targeting transforming growth factor beta receptor 1 (TGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2) The first patient with head and neck squamous cell carcinoma was dosed in the Phase 2a clinical trial of TU2218 The Phase 2a trial of TU2218 starts with head and neck squamous cell carcinoma, as well as biliary tract cancer patients. It will be later expanded to colorectal cancer patients BOSTON and SEONGNAM, South Korea, Oct. 4, 2024 /PRNewswire/ -- TiumBio Co., Ltd. (Kosdaq: 321550), a clinical-stage biopharmaceutical company focused on discovering and developing innovative therapeutics for patients with rare and incurable diseases, announced today that the first patient has been dosed in its Phase 2 clinical trial of TU2218. TU2218 is a novel oral dual inhibitor targeting TGFR1 and VEGFR2. TGF-ß and VEGF pathways are known to suppress the activity of immune checkpoint inhibitors (ICIs), so TU2218 is expected to improve the efficacy of ICIs by blocking the two pathways. In Phase 1a and 1b clinical trials, TiumBio evaluated the safety, pharmacokinetics, and pharmacodynamics of TU2218 as a monotherapy and in combination with Keytruda (pembrolizumab) in 41 patients with advanced solid tumors. These profiles were used to determine the dose levels for Phase 2 trials. The Phase 2a trial is designed to assess the safety and efficacy of TU2218 in combination with Keytruda in patients with head and neck squamous cell carcinoma (HNSCC), biliary tract cancer (BTC), and colorectal cancer (CRC). The Phase 2 trial begins at Seoul National University Hospital and Asan Medical Center in South Korea, which is planned to expand to hospitals in the United States. The first dose was administered to an HNSCC patient. HNSCC refers to malignant tumors that occur in the oral cavity, throat, larynx, or salivary glands. The standard treatment typically involves surgery and radiation therapy. According to Global Data, as of 2023, the number of HNSCC patients worldwide is estimated to be around 610,000, and it is expected to exceed 670,000 by 2030. "HNSCC is a disease with a high unmet medical need, as the average survival rate for first-line treatments is known to be only about one year," said Hun-taek Kim, Ph.D., MBA, CEO of TiumBio. "We have selected cancer types for the Phase 2 clinical trial based on other trials that demonstrated strong anti-cancer effects from targeting TGF- ß or VEGF pathways. Our goal is to develop TU2218 as a first-line treatment for HNSCC," he added. In the Phase 1b trial, among 10 patients with advanced solid tumors who received a 195mg daily dose (the determined dose for Phase 2) of TU2218 with Keytruda, three patients achieved partial response (PR) and five patients had stable disease (SD), yielding an 80% disease control rate (DCR). About TiumBio Co., Ltd. TiumBio (Kosdaq: 321550) is a clinical-stage biopharmaceutical company focused on the discovery and development of innovative therapeutics for patients with rare and incurable diseases. Its mission is to expand the hope and happiness of mankind through our science. TiumBio boasts three leading pipeline assets: merigolix (code name: TU2670), TU2218, and TU7710, all in various stages of clinical development. Merigolix is a once-daily, oral GnRH receptor antagonist being developed for the treatment of endometriosis and uterine fibroids and is undergoing in global Phase 2 clinical trials. TU2218 is a first-in-class oral immune-oncology therapy targeting TGF-β and VEGF pathways to promote response rates in cancer patients when used in combination with immune checkpoint inhibitors. TU7710 is a novel rFVIIa designed to extend its half-life in order to provide more clinical benefits to hemophilia patients with inhibitors. With its expertise in drug development, TiumBio is committed to the discovery and development of innovative treatments to ease the burden of debilitating diseases. For further information, visit our website at and connect with us on LinkedIn. Contacts: Junseok Jang, Head of Corporate Communications & Investor Relations [email protected] Suna Cho, Manager, Corporate Communications & Investor Relations [email protected] Da-ye Song, Manager, Corporate Communications & Investor Relations [email protected] SOURCE TiumBio WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED