Signal Transduction and Targeted Therapy最新文献

{"title":"Chemical inducers of proximity: precision tools for apoptosis in transcriptional regulation","authors":"Kai Huang","doi":"10.1038/s41392-024-02089-4","DOIUrl":"https://doi.org/10.1038/s41392-024-02089-4","url":null,"abstract":"<p>A recent study published in <i>Science</i> by Sarott et al. introduces CDK-transcriptional/epigenetic chemical inducers of proximity (CDK-TCIPs), a novel therapeutic approach that reactivates pro-apoptotic genes to selectively kill BCL6-overexpressing lymphoid cancers. This gain-of-function strategy represents a significant advancement in targeting transcrptional dysregulation.¹</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"15 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase 2 pilot study of umbilical cord blood infusion as an adjuvant consolidation therapy in elderly patients with acute myeloid leukemia","authors":"Jinzeng Wang, Xiaoyang Li, Ping Liu, Yao Dai, Hongming Zhu, Yunxiang Zhang, Min Wu, Yunying Yao, Mingzhu Liu, Shuting Yu, Fangying Jiang, Shuai Wang, Haoran Mu, Bo Jiao, Hua Yan, Wen Wu, Yang Shen, Junming Li, Shengyue Wang, Ruibao Ren","doi":"10.1038/s41392-024-02065-y","DOIUrl":"https://doi.org/10.1038/s41392-024-02065-y","url":null,"abstract":"<p>Acute myeloid leukemia (AML) is an aging-related malignancy, with patients aged ≥60 years old facing significantly poorer prognosis. Umbilical cord blood (UCB) has emerged as a promising source with effective anti-aging roles. Here, we conducted a prospective, phase 2, single-arm trial of UCB infusion as an adjuvant consolidation therapy in elderly AML patients (ChiCTR-OPC-15006492). A total of 51 patients were enrolled (median age 66 years; range, 60–75) and received two cycles of consolidation chemotherapy combined with UCB infusion. At a median follow-up of 27.3 months (range, 9.3–100), the median overall survival (OS) was not yet reached and the median event-free survival (EFS) was 72.2 months (range, 5.4–100). The 2-year OS and EFS rates were 76.9% and 62.8%, respectively. No acute graft-versus-host disease (aGVHD) or toxicity-related death occurred in any patient. The median times to platelet and neutrophil recovery were 11.5 days (range, 6–17) and 12.2 days (range, 0–21), respectively. Single-cell RNA sequencing (scRNA-seq) identified enhanced anti-tumor and anti-aging properties of UCB, manifested through activation of immune responses and telomere synthesis/maintenance. These findings suggest that UCB infusion is an effective and safe post-remission adjuvant therapy for elderly AML patients. This study provides evidence that anti-aging therapy may serve as a new and promising dimension in combined cancer treatment.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"66 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophages promote pre-metastatic niche formation of breast cancer through aryl hydrocarbon receptor activity","authors":"Xu Jiang, Jiaqi Wang, Liangyu Lin, Liming Du, Yayun Ding, Fanjun Zheng, Hongzhen Xie, Yu Wang, Mingyuan Hu, Benming Liu, Muhan Xu, Jingjie Zhai, Xuefeng Wang, Jiayin Ye, Wei Cao, Chao Feng, Jingyi Feng, Zongliu Hou, Mingyao Meng, Ju Qiu, Qing Li, Yufang Shi, Ying Wang","doi":"10.1038/s41392-024-02042-5","DOIUrl":"https://doi.org/10.1038/s41392-024-02042-5","url":null,"abstract":"<p>Macrophages that acquire an immunosuppressive phenotype play a crucial role in establishing the pre-metastatic niche (PMN), which is essential for facilitating breast cancer metastasis to distant organs. Our study showed that increased activity of the aryl hydrocarbon receptor (AHR) in lung macrophages plays a crucial role in establishing the immunosuppressive PMN in breast cancer. Specifically, AHR activation led to high expression of PD-L1 on macrophages by directly binding to the promoter of <i>Pdl1</i>. This upregulation of PD-L1 promoted the differentiation of regulatory T cells (Tregs) within the PMN, further enhancing immunosuppressive conditions. Mice with <i>Ahr</i> conditional deletion in macrophages had reduced lung metastasis of breast cancer. The elevated AHR levels in PMN macrophages were induced by GM-CSF, which was secreted by breast cancer cells. Mechanistically, the activated STAT5 signaling pathway induced by GM-CSF prevented AHR from being ubiquitinated, thereby sustaining its activity in macrophages. In breast cancer patients, the expression of <i>AHR</i> and <i>PD-L1</i> was correlated with increased Treg cell infiltration, and higher levels of <i>AHR</i> were associated with a poor prognosis. These findings reveal that the crosstalk of breast cancer cells, lung macrophages, and Treg cells via the GM-CSF-STAT5-AHR-PD-L1 cascade modulates the lung pre-metastatic niche during breast cancer progression.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"258 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-reported outcomes of rezvilutamide versus bicalutamide in combination with androgen deprivation therapy in high-volume metastatic hormone-sensitive prostate cancer patients (CHART): a randomized, phase 3 study","authors":"Hongkai Wang, Shusuan Jiang, Hong Luo, Fangjian Zhou, Dalin He, Lulin Ma, Hongqian Guo, Chaozhao Liang, Tie Chong, Jun Jiang, Zhiwen Chen, Yong Wang, Qing Zou, Ye Tian, Jun Xiao, Jian Huang, Jinchao Chen, Qiang Dong, Xiaoping Zhang, Hanzhong Li, Xinfeng Yang, Jianpo Lian, Wenliang Wang, Dingwei Ye","doi":"10.1038/s41392-024-02064-z","DOIUrl":"https://doi.org/10.1038/s41392-024-02064-z","url":null,"abstract":"<p>The randomized phase 3 CHART trial (NCT03520478) revealed that rezvilutamide (REZ) plus androgen deprivation therapy (ADT) in high-volume, metastatic, hormone-sensitive prostate cancer (mHSPC) significantly enhanced radiographic progression-free and overall survival than bicalutamide (BIC)-ADT. Accordingly, we examined patient-reported outcomes (PROs) results, which were exploratory endpoints in the CHART trial. The patients were randomly allocated to receive REZ-ADT or BIC-ADT in a 1:1 ratio. The PROs were evaluated with the Brief Pain Inventory-Short Form (BPI-SF) and the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaires. Both study groups displayed comparable baseline pain scores and functional status. Patients administered REZ-ADT had an extended time to progression of worst pain intensity in comparison to those treated with BIC-ADT (25th percentile, 9.2 [95% CI 7.4–16.6] vs. 6.4 months [95% CI 5.5–8.3]; HR 0.75 [95% CI 0.57–0.97]; <i>p</i> = 0.026). Similarly, patients received REZ-ADT exhibited a delayed time to progression of pain interference in comparison to those receiving BIC-ADT (25th percentile, 20.2 [95% CI 12.9–31.3] vs. 10.2 months [95% CI 7.4–11.1]; HR 0.70 [95% CI 0.52–0.93]; <i>p</i> = 0.015). Additionally, the REZ-ADT group demonstrated a prolonged delay in the deterioration of the total score on the FACT-P questionnaire (25th percentile, 12.8 [95% CI 7.4–20.3] vs. 6.0 months [95% CI 4.6–9.2]; HR 0.66 [95% CI 0.50–0.86]; <i>p</i> = 0.002), as well as most of the FACT-P subscale scores, in comparison to the BIC-ADT group. In conclusion, REZ-ADT is superior to BIC-ADT regarding the pain alleviation and enhancement of functional scales for high-volume mHSPC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"49 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in calcium-sensing receptor modulation: biased signaling and therapeutic potential","authors":"Luisa Uhlmann, Ulf Wagner","doi":"10.1038/s41392-024-02084-9","DOIUrl":"https://doi.org/10.1038/s41392-024-02084-9","url":null,"abstract":"<p>In a recent study published in <i>Science</i>, Liu and colleagues used computational ultra-large library docking to discover new chemotypes acting as positive allosteric modulators (PAM) of the Calcium-Sensing Receptor (CaSR),¹ which bind the receptor with very high affinity and shows evidence of biased signaling, i.e. the preferential activation of one signaling pathway over others, compared to the receptor’s natural ligands. Importantly, the in vivo test of one substance (‘54159) did not induce hypocalcemia, which is an advantage over FDA-approved calcimimetics, which are limited in clinical practice due to their potential to disrupt calcium homeostasis and cause hypocalcemia.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"120 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noninvasive early identification of durable clinical benefit from immune checkpoint inhibition: a prospective multicenter study (NCT04566432)","authors":"Xinghao Ai, Bo Jia, Zhiyi He, Junping Zhang, Minglei Zhuo, Jun Zhao, Zhe Wang, Jiexia Zhang, Zaiwen Fan, Xiaotong Zhang, Chong Li, Feng Jin, Ziming Li, Xia Ma, Hao Tang, Xiang Yan, Wei Li, Yuanyuan Xiong, Huan Yin, Rongrong Chen, Shun Lu","doi":"10.1038/s41392-024-02060-3","DOIUrl":"https://doi.org/10.1038/s41392-024-02060-3","url":null,"abstract":"<p>Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for patients with non-small cell lung cancer (NSCLC). In spite of durable responses in some patients, many patients develop early disease progression during the ICI treatment. Thus, early identification of patients with no durable benefit would facilitate the clinical decision for these patients. In this prospective, multicenter study, 101 non-<i>EGFR/ALK</i> patients who received ICI treatment were enrolled after screening 328 stage III-IV NSCLC patients. At the date of cutoff, 83 patients were eligible for ICI efficacy evaluation, with 56 patients having progress-free survival (PFS) over 6 months, which was defined as durable clinical benefit (DCB). A multimodal model was established by integrating normalized bTMB, early dynamic of ctDNA and the first RECIST response. This model could robustly predict DCB with area under the curve (AUC) of 0.878, sensitivity of 79.2% at 86.4% specificity (accuracy = 80.0%). This model was further validated in the independent cohort of the DIREct-On study with AUC of 0.887, sensitivity of 94.7% at 85.3% specificity (accuracy = 90.3%). Patients with higher predict scores had substantially longer PFS than those with lower scores (training cohort: median PFS 13.6 vs 4.2 months, <i>P</i> &lt; 0.001, HR = 0.24; validation cohort: median PFS 11.0 vs 2.2 months, <i>P</i> &lt; 0.001, HR = 0.17). Taken together, these results demonstrate that integrating early changes of ctDNA, normalized bTMB, and the first RECIST response can provide accurate, noninvasive, and early prediction of durable benefits for NSCLC patients treated with ICIs. Further prospective studies are warranted to validate these findings and guide clinical decision-making for optimal immunotherapy in NSCLC patients.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"38 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Addition of SHR-1701 to first-line capecitabine and oxaliplatin (XELOX) plus bevacizumab for unresectable metastatic colorectal cancer","authors":"Miao-Zhen Qiu, Yuxian Bai, Jufeng Wang, Kangsheng Gu, Mudan Yang, Yifu He, Cheng Yi, Yongdong Jin, Bo Liu, Feng Wang, Yu-kun Chen, Wei Dai, Yingyi Jiang, Chuanpei Huang, Rui-Hua Xu, Hui-Yan Luo","doi":"10.1038/s41392-024-02063-0","DOIUrl":"https://doi.org/10.1038/s41392-024-02063-0","url":null,"abstract":"<p>This phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β, in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxaliplatin) as a first-line treatment for unresectable metastatic colorectal cancer (mCRC). In this phase 2 study, a total of 62 patients with untreated, histologically confirmed colorectal adenocarcinoma and no prior systemic therapy for metastatic disease were enrolled. Patients received SHR-1701 (30 mg/kg), bevacizumab (7.5 mg/kg), and oxaliplatin (130 mg/m²) intravenously on day 1, along with oral capecitabine (1 g/m² twice daily) on days 1–14 of 21-day cycles. Up to eight induction cycles were administered, followed by maintenance therapy for responders or those with stable disease. The primary endpoints were safety and objective response rate (ORR) per RECIST v1.1. The combination achieved an ORR of 59.7% and a disease control rate (DCR) of 83.9%. Median progression-free survival (PFS) was 10.3 months (95% CI: 8.3–13.7), with 6- and 12-month PFS rates of 77.2% and 41.3%, respectively. The estimated 12-month overall survival (OS) rate was 67.7%. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 59.7% of patients, with anemia and neutropenia (8.1% each) being the most common. Retrospective DNA sequencing revealed that high tumor mutational burden, neo-antigens, and SBS15 enrichment correlated with better responses. Elevated baseline lactate dehydrogenase was linked to shorter PFS. SHR-1701 combined with XELOX and bevacizumab demonstrated a manageable safety profile and potent antitumor activity in unresectable mCRC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"51 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridge over troubled cells: bone marrow stromal cells transfer mitochondria to boost T cells","authors":"Lars Fabian Prinz, Roland Tillmann Ullrich, Markus Martin Chmielewski","doi":"10.1038/s41392-024-02079-6","DOIUrl":"https://doi.org/10.1038/s41392-024-02079-6","url":null,"abstract":"<p>In an article published in <i>Cell</i> in September 2024, Baldwin and colleagues present a bone marrow stromal cell (BMSC) based mitochondrial transfer platform to combat mitochondrial dysfunction or scarcity in human T cells ex-vivo.¹ This thorough and methodically diverse investigation results in a promising technology at a time when adoptive T cell therapies seem to run against a wall of T cell exhaustion and dysfunction in treatments targeting solid tumors.²</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"21 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Next-generation mpox vaccines: efficacy of mRNA-1769 compared to modified vaccinia virus Ankara in non-human primates","authors":"Leonie Mayer, Leonie M. Weskamm, Marylyn M. Addo","doi":"10.1038/s41392-024-02092-9","DOIUrl":"https://doi.org/10.1038/s41392-024-02092-9","url":null,"abstract":"<p>Correction to: <i>Signal Transduction and Targeted Therapy</i> (2024) 9:327; https://doi.org/10.1038/s41392-024-02058-x; Article published online 20 November 2024</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"29 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and biomarker analyses of SHR-1701 combined with famitinib in patients with previously treated advanced biliary tract cancer or pancreatic ductal adenocarcinoma: a phase II trial","authors":"Lixia Yi, Haoqi Pan, Zhouyu Ning, Litao Xu, Hena Zhang, Longfei Peng, Yaowu Liu, Yifan Yang, Waimei Si, Ying Wang, Xiaoyan Zhu, Shenglin Huang, Zhiqiang Meng, Jing Xie","doi":"10.1038/s41392-024-02052-3","DOIUrl":"https://doi.org/10.1038/s41392-024-02052-3","url":null,"abstract":"<p>Advanced biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC) have poor prognoses and limited treatment options. Here, we conducted this first-in-class phase II study to evaluate the efficacy and safety of SHR-1701, a bifunctional fusion protein targeting programmed death-ligand 1 (PD-L1) and transforming growth factor-beta (TGF-β), combined with famitinib, a multi-targeted receptor tyrosine kinase inhibitor, in patients with advanced BTC or PDAC who failed previous standard treatment (trial registration: ChiCTR2000037927). Among 51 enrolled patients, the BTC cohort showed an objective response rate (ORR) of 28% (including 2 complete responses) and a disease control rate (DCR) of 80%, with a median progression-free survival (mPFS) of 5.1 months and a median overall survival (mOS) of 16.0 months. In the PDAC cohort, the ORR was 15% (2 complete responses), with a DCR of 60%, and the mPFS and mOS were 2.1 months and 5.3 months, respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 29.4% of patients, with no grade 5 TRAEs reported. Exploratory analyses revealed that primary tumor resection history, peripheral blood immunophenotype changes, and distinct immune-metabolic profiles were associated with treatment benefits. An immune/metabolism score integrating the features of six genes was developed as a predictive biomarker for immunotherapy response in multiple cohorts, allowing for the selection of patients most likely to experience positive outcomes from this therapy regimen. In conclusion, our study provides proof-of-concept data supporting the potential of SHR-1701 plus famitinib as an effective and safe subsequent-line therapy for refractory BTC and PDAC, highlighting the promise of targeting PD-L1, TGF-β, and angiogenesis pathways simultaneously.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"21 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}