This phase II trial tests how well photoradiation with verteporfin and pembrolizumab plus standard of care chemotherapy works in treating patients with pancreatic cancer that cannot be removed by surgery (unresectable), that has spread to nearby tissue or lymph nodes (locally advanced) or to other places in the body (metastatic). Photoradiation uses light activated drugs, such as verteporfin, that become active when exposed to light. These activated drugs may kill tumor cells. Vertoporfin may also increase tumor response to immunotherapy. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX), work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Photoradiation with verteporfin and pembrolizumab plus standard of care chemotherapy may kill more tumor cells in patients with unresectable, locally advanced or metastatic pancreatic cancer.

开始日期2024-10-30

申办/合作机构

Mayo Clinic

[+1]

100 项与 YAP1 x TEAD 相关的临床结果

登录后查看更多信息

100 项与 YAP1 x TEAD 相关的转化医学

登录后查看更多信息

0 项与 YAP1 x TEAD 相关的专利（医药）

登录后查看更多信息

340

项与 YAP1 x TEAD 相关的文献（医药）

2024-12-01·Journal of Computer-Aided Molecular Design

Computational design and experimental confirmation of a disulfide-stapled YAP helixα1-trap derived from TEAD4 helical hairpin to selectively capture YAP α1-helix with potent antitumor activity

Article

作者: Li, Kaipeng ; Liu, Lijun

Human Hippo signaling pathway is an evolutionarily conserved regulator network that controls organ development and has been implicated in various cancers. Transcriptional enhanced associate domain-4 (TEAD4) is the final nuclear effector of Hippo pathway, which is activated by Yes-associated protein (YAP) through binding to two separated YAP regions of α1-helix and Ω-loop. Previous efforts have all been addressed on deriving peptide inhibitors from the YAP to target TEAD4. Instead, we herein attempted to rationally design a so-called 'YAP helix^α1-trap' based on the TEAD4 to target YAP by using dynamics simulation and energetics analysis as well as experimental assays at molecular and cellular levels. The trap represents a native double-stranded helical hairpin covering a specific YAP-binding site on TEAD4 surface, which is expected to form a three-helix bundle with the α1-helical region of YAP, thus competitively disrupting TEAD4-YAP interaction. The hairpin was further stapled by a disulfide bridge across its two helical arms. Circular dichroism characterized that the stapling can effectively constrain the trap into a native-like structured conformation in free state, thus largely minimizing the entropy penalty upon its binding to YAP. Affinity assays revealed that the stapling can considerably improve the trap binding potency to YAP α1-helix by up to 8.5-fold at molecular level, which also exhibited a good tumor-suppressing effect at cellular level if fused with TAT cell permeation sequence. In this respect, it is considered that the YAP helix^α1-trap-mediated blockade of Hippo pathway may be a new and promising therapeutic strategy against cancers.

2024-12-01·Cellular and Molecular Life Sciences

Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication

Article

作者: Ibberson, David ; Schmitt, Jennifer ; Poth, Tanja ; Pedrini, Fabiola ; Bissinger, Michaela ; Guo, Te ; Schirmacher, Peter ; Tóth, Marcell ; Colucci, Silvia ; Marhenke, Silke ; Cheng, Wenxiang ; Breuhahn, Kai ; Vogel, Arndt ; Longerich, Thomas ; Liu, Kaijing ; Birner, Patrizia ; Damle-Vartak, Amruta ; Weiler, Sofia M E ; Angel, Peter ; Muckenthaler, Martina U ; Dropmann, Anne ; Pinna, Federico ; Wan, Shan ; Wehling, Lilija ; Rose, Fabian ; Lam, Macrina ; Ali, Adnan ; Heikenwälder, Mathias ; Dooley, Steven

AbstractIntroductionThe Hippo pathway and its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are targets for cancer therapy. It is important to determine if the activation of one factor compensates for the inhibition of the other. Moreover, it is unknown if YAP/TAZ-directed perturbation affects cell–cell communication of non-malignant liver cells.Materials and MethodsTo investigate liver-specific phenotypes caused by YAP and TAZ inactivation, we generated mice with hepatocyte (HC) and biliary epithelial cell (BEC)-specific deletions for both factors (YAPKO, TAZKO and double knock-out (DKO)). Immunohistochemistry, single-cell sequencing, and proteomics were used to analyze liver tissues and serum.ResultsThe loss of BECs, liver fibrosis, and necrosis characterized livers from YAPKO and DKO mice. This phenotype was weakened in DKO tissues compared to specimens from YAPKO animals. After depletion of YAP in HCs and BECs, YAP expression was induced in non-parenchymal cells (NPCs) in a cholestasis-independent manner. YAP positivity was detected in subgroups of Kupffer cells (KCs) and endothelial cells (ECs). The secretion of pro-inflammatory chemokines and cytokines such as C-X-C motif chemokine ligand 11 (CXCL11), fms-related receptor tyrosine kinase 3 ligand (FLT3L), and soluble intercellular adhesion molecule-1 (ICAM1) was increased in the serum of YAPKO animals. YAP activation in NPCs could contribute to inflammation via TEA domain transcription factor (TEAD)-dependent transcriptional regulation of secreted factors.ConclusionYAP inactivation in HCs and BECs causes liver damage, and concomitant TAZ deletion does not enhance but reduces this phenotype. Additionally, we present a new mechanism by which YAP contributes to cell–cell communication originating from NPCs.

2024-11-01·Cancer Letters

The role of Hippo/YAP1 in cancer-associated fibroblasts: Literature review and future perspectives

Review

作者: Yao, Xiaodan ; Athavale, Dipti ; Balch, Curt ; Song, Shumei ; Zhang, Yanting

Cancer-associated fibroblasts (CAFs) are activated fibroblasts that play a role in numerous malignant phenotypes, including hyperproliferation, invasion, and metastasis. These phenotypes correlate with activity of the Hippo pathway oncoprotein, Yes-associated protein-1 (YAP1), and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ). YAP1/TAZ are normally involved in organ growth, under the regulation of various kinases and upon phosphorylation, are retained in the cytoplasm by chaperone proteins, leading to their proteasomal degradation. In CAFs and tumor cells, however, a lack of YAP1 phosphorylation results in its translocation to the nucleus, binding to TEAD transcription factors, and activation of mitogenic pathways. In this review we summarize the literature discussing the central role of YAP1 in CAF activation, the upstream cues that promote YAP1-mediated CAF activation and extracellular matrix remodeling, and how CAFs mediate tumor-stroma crosstalk to support progression, invasion and metastasis in various cancer models. We further highlight YAP1⁺CAFs functions in modulating an immunosuppressive tumor microenvironment and propose evaluation of several YAP1 targets regarding their role in regulating intra-tumoral immune landscapes. Finally, we propose that co-administration of YAP1- targeted therapies with immune checkpoint inhibitors can improve therapeutic outcomes in patients with advanced tumors.

项与 YAP1 x TEAD 相关的新闻（医药）

2024-10-05

·生物探索

EMBO J | 周兆才/焦石/安利伟发现辅因子介导的基因转录抑制性相分离现象并研发诱导TEAD4抑制性相分离的抗肿瘤干预策略

引言相分离是生物大分子在特定状态下的一种特殊的自发凝聚现象，在基因转录、表观遗传、信号转导等细胞正向生长过程中发挥关键调节作用，但目前对于生物大分子在肿瘤等乏营养背景下相分离现象及其功能作用仍缺乏了解，阻碍了靶向相分离相关的抗肿瘤干预策略的研发。 2024年10月2日，复旦大学周兆才/焦石及同济大学附属第十人民医院安利伟联合团队在EMBO J上发表了文章A cofactor-induced repressive type of transcription factor condensation can be induced by synthetic peptides to suppress tumorigenesis。该研究首次发现了一种由葡萄糖剥夺引起的与抑制基因转录相关的生物大分子相分离现象，并以Hippo信号通路下游的转录因子TEAD4为例，鉴定了调控其抑制性相分离的辅助因子并解释其对基因转录调控的分子机制，并研发了基于多肽的靶向诱导TEAD4抑制性相分离的抗肿瘤干预策略。该团队前期系统性地研究了Hippo信号通路的调控网络和分子机制，探究了其在胃肠道肿瘤发生过程中的病理作用，发现了YAP拮抗蛋白VGLL4以及激活蛋白IRF3等调控肿瘤发生发展的功能与机制，并设计发展了靶向抗癌的治疗性多肽及小分子化合物（Cancer Cell 2014/2020; Cell Res 2014; Nat Commun 2017; J Exp Med 2018）。为了探究乏营养等肿瘤特征对转录因子相分离的调节效应，该团队利用高内涵成像对超过700多个转录因子的文库进行不同条件的系统筛选，发现葡萄糖剥夺可诱导包括TEAD4, EWSH、RFXDC1、GTF2A1L、C16orf5、ZNF800和ELF1等多个转录因子形成生物大分子凝聚体，且这些相分离与转录抑制性表观修饰如H3K27me3存在明显共定位，因此把这一现象命名为转录因子的抑制性相分离现象（Repressive TF condensation）。在此基础上，该团队以TEAD4为例，发现VGLL4和RFXANK等辅因子可以介导TEAD4的寡聚并促进抑制型相分离生成。与前期已知的YAP/TAZ介导的TEAD4转录激活相分离相比，本研究揭示的TEAD4抑制型相分离可导致DNA/染色质聚集和缠绕从而触发细胞死亡。受此启发，该团队结合前期解析的VGLL4-TEAD4晶体结构，创造性设计了一个模拟VGLL4与TEAD4结合基序衍生肽（GLUP）。体内外实验发现该GLUP多肽能够特异性诱导TEAD4抑制性相分离发生，进而抑制基因转录和细胞生长，在遗传和异种移植胃癌小鼠模型中显示出很强的抗肿瘤作用。模式图（Credit: EMBO J）该研究的发现揭示了生物大分子相分离对细胞生长调控的新型模式和分子机制，为靶向相分离的肿瘤治疗提供新思路。同时，这项研究创新性地围绕调控转录因子相分离类型抗肿瘤药物的设计，诱导抑制型相分离，为肿瘤发生的病理机制及靶向干预策略提供了新的策略和先导药物。参考文献 https://doi.org/10.1038/s44318-024-00257-4 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

临床结果

2024-09-19

·今日头条

可提高化疗药物疗效！上海交通大学刘辰莹/杜鹏团队：结直肠癌的联合治疗新策略

【导读】转录酶DDX21对于核糖体的生成至关重要，在结直肠癌（CRC）中表达上调，但DDX21的失调机制以及其在CRC中促进肿瘤形成的机制尚不为人所知。 9月17日，上海交通大学刘辰莹/杜鹏研究团队在期刊《Oncogene》上发表了题为“The RNA helicase DDX21 activates YAP to promote tumorigenesis and is transcriptionally upregulated by β-catenin in colorectal cancer”的研究论文，本研究中，研究人员发现DDX21是β-catenin的一个直接转录靶基因，并介导了β-catenin在结直肠癌中的促癌功能。结直肠癌组织中DDX21的表达与β-catenin的表达及活性相关，DDX21高表达与结直肠癌患者的不良预后相关。DDX21的缺失导致细胞质易位和YAP转录活性降低，抑制结直肠癌细胞的增殖和迁移，而YAP的重新激活可部分挽救这一作用。研究人员还发现核糖体应激可能通过ZAKα-MKK4/7-JNK轴上调DDX21的表达，诱导LATS的下调和YAP的激活。总之，本研究揭示了结直肠癌中DDX21的转录激活机制以及核糖体应激反应中YAP的激活，表明了涉及诱导核糖体应激和YAP抑制的联合治疗的潜力。 https://www.nature.com/articles/s41388-024-03160-8#Abs1 背景知识 01 DEAD-box RNA解旋酶调节RNA结构的形成，在各种生物过程中发挥重要作用，包括核糖体的生物发生，转录和翻译。DDX21是核仁DEAD-box RNA解旋酶家族成员，并首先被鉴定为c- jun依赖转录的转录辅因子。近年来的研究阐明了DDX21协调基因转录和核糖体RNA加工的机制，揭示了DDX21在核糖体生物发生的多个步骤中的关键作用。此外，DDX21可解析基因组R环，并在基因转录过程中协同SIRT7维持基因组稳定性。尤其是，DDX21只有在适当的表达水平才能促进双链断裂(DSB)修复。DDX21的异常高表达延迟了同源重组(HR)修复，导致基因组不稳定和随后的肿瘤发生。癌症分析表明，DEAD-box RNA解旋酶DDX21的表达在CRC的mRNA水平显著上调，促进CRC的转移和肿瘤生长。然而，在结直肠癌中，DDX21 mRNA表达上调的转录激活机制以及DDX21的下游效应分子在肿瘤发生和进展中的作用仍不清楚。 Hippo通路是一个保守的信号通路，参与哺乳动物的器官大小控制和组织稳态。转录共激活因子YAP/TAZ是Hippo通路的主要下游效应因子。YAP/TAZ的异常激活导致多种肿瘤的发生和侵袭表型，包括CRC。YAP/TAZ可以调控基因转录和细胞行为以应对多种细胞刺激和胁迫，如渗透胁迫、能量胁迫、内质网应激、氧化应激和热应激。核糖体应激(RQC)又称核糖体毒性应激(ISR)，是指核糖体功能和生物发生的损害，最终导致各种应激信号的激活，包括P53、核糖体毒性应激反应(RSR)、核糖体相关质量控制RQC)和综合应激反应(ISR)。RSR是一种由MAP3K20激酶ZAKα启动的丝裂原活化蛋白(MAP)激酶信号级联，并激活与应激相关的MAP激酶p38和JNK。然而，RSR和Hippo通路之间的生物学相关性以及ZAKα在CRC中对YAP活性的调节作用仍然不清楚。 DDX21促进YAP在结直肠癌发生中的致癌功能 02 之前的研究已经表明，作为7SK snRNP的重要组成部分，DDX21可以调节RNA的二级结构和核糖体RNA（rRNA）的合成，并促进转录延伸。为了探究DDX21在结直肠癌细胞中的转录效应，研究人员对敲除和对照HCT-116细胞进行了RNA-seq分析。与对照细胞相比，DDX21敲除HCT-116细胞中下调了69个基因，上调了118个基因（log2FC>1, p<0.05）。尤其是，基因集富集分析（GSEA）揭示，YAP靶基因集在DDX21敲除HCT-116细胞中的差异表达基因中富集。qPCR分析进一步证实，DDX21敲除HCT-116和RKO细胞中经典的YAP靶基因（如CTGF、CYR61、THBS1和AXL）的mRNA水平降低。相反，稳定过表达DDX21增加了YAP靶基因的表达。与上述结果一致，蛋白质免疫印迹实验分析显示，DDX21敲除细胞中磷酸化YAP-Ser127的水平升高。研究人员还观察到DDX21敲除HCT-116细胞胞质中出现弥散的YAP染色，这反映了YAP的胞质转位。值得注意的是，研究人员没有检测到DDX21与YAP/TAZ/TEAD复合物的相互作用（未显示数据）。因此，尽管有报道表明YAP控制转录延伸，但DDX21可能不直接参与YAP/TEAD靶基因的转录调控。YAP激活在多种癌症中常见，包括结直肠癌。因此，研究人员探讨了YAP是否介导了DDX21在CRC中的促癌效应。为此，研究人员建立了DDX21敲低HCT-116细胞，并过表达了恒定活性的YAP5SA。正如预期的那样，DDX21敲低抑制HCT-116细胞的增殖、克隆形成和细胞迁移的作用被过表达恒定活性的YAP5SA逆转。此外，研究人员建立了DDX21过表达的HCT-116和HIEC-6细胞，并进行了YAP敲低。正如预期的那样，YAP敲低消除了DDX21过表达诱导的YAP靶基因的上调表达。持续观察发现，DDX21过表达可显著增强HCT-116和HIEC-6细胞的增殖、克隆形成和细胞迁移能力，而YAP敲低则可显著降低上述效应。综上所述，这些数据表明DDX21在结直肠癌中发挥促癌作用，可能通过激活Hippo通路下游效应分子YAP来实现。 DDX21会增强YAP的活性，促进结直肠癌的发生研究小结 03 综上，本研究揭示了β-catenin在结直肠癌中转录激活DDX21, YAP/TEAD在响应核糖体应激时被激活，强调了靶向结直肠癌核仁DDX21和YAP/TEAD的联合策略的治疗潜力。【参考资料】 https://www.nature.com/articles/s41388-024-03160-8#Abs1 【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 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会 🕓 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

2024-05-13

·PRNewswire

Beactica Therapeutics to present breakthrough in YAP-TEAD programme at the Hippo Pathway Drug Development Summit 2023

STOCKHOLM, May 16, 2023 /PRNewswire/ -- Beactica Therapeutics AB, the Swedish precision oncology company, today announced that its YAP-TEAD programme has been selected for an oral presentation at the 2nd Hippo Pathway Targeted Drug Development Summit 2023. The conference will take place on May 23-35, 2023, in Boston, Massachusetts. Dr Peter Brandt, Head of Chemistry, will present a talk entitled Specific Degraders of TEADs Based on Interface 3 Binding on Thursday May 25, 2023, at 2:00 – 2:30 PM in the Boston Park Plaza. The presentation will showcase a breakthrough in the development of novel cell-active targeted degraders of TEAD, with therapeutic potential against multiple types of life-threatening cancers. The degraders developed are based on previously generated proprietary inhibitors of the YAP–TEAD protein–protein interaction. These have now been developed into bifunctional compounds with the additional ability to induce selective degradation of TEAD through the proteasome, the cell's own waste disposal system. The achievement provides a strong validation of the capabilities Beactica has built for targeted protein degradation. Compared to traditional inhibitors, targeted protein degraders have the potential to achieve a more potent and durable therapeutic effect. The Hippo Pathway Targeted Drug Development Summit is the first and only industry-led forum, uniting a community focused on progressing functional understanding, and realizing the potential of the Hippo signaling pathway to enhance the discovery, translation and clinical development of safe and effective drugs in oncology, regenerative medicine and beyond. About YAP–TEAD YAP1 (Yes-associated protein 1) is a coactivator that together with TEAD 1–4 (TEA Domain) transcription factors play key roles in the Hippo signalling pathway that regulate cell proliferation, apoptosis, and stemness. Dysregulation of the Hippo pathway and subsequent activation of TEAD has been reported in a wide range of cancers such as squamous cell carcinoma, head and neck, gynaecological, and gastrointestinal cancers. The first clinical proof-of-concept for drugging the Hippo–YAP–TEAD pathway was recently achieved with the TEAD inhibitor VT3989, which was presented at the American Association for Cancer Research (AACR) Annual Meeting in April 2023. About Beactica Therapeutics Beactica Therapeutics AB is a privately held precision oncology company committed to the fight against cancer. The company is advancing a pipeline of novel small molecule therapeutics with a focus to treat genetically defined cancers with significant unmet medical need. Beactica's approach is centered around targeting synthetically lethal disease proteins with allosteric modulators and targeted protein degraders. Beactica deliver value to patients and shareholders by advancing its programmes to clinical proof of concept. For more information, please visit www.beactica.com.

AACR会议