Translational Oncology最新文献

{"title":"Response Gene to Complement 32 is associated with poor patient survival and an inflamed tumor-immune microenvironment in clear cell renal cell carcinoma.","authors":"Lingling Li, Xiaocui Bu, Shuhui Wang, Yan Liu, Chongdao Chen, Wei Zhang, Peng Zhao","doi":"10.1016/j.tranon.2024.102248","DOIUrl":"10.1016/j.tranon.2024.102248","url":null,"abstract":"<p><p>It has been well established that tumor-infiltrating lymphocytes (TILs) play a critical role in the pathogenesis and progression of clear cell renal cell carcinoma (ccRCC). However, the mechanism on the interactions between TILs and tumor cells in the tumor-immune microenvironment remains unclear. In the present study, the expression of Response Gene to Complement 32 (RGC-32) was evaluated using immunohistochemistry. We analyzed the associations of RGC-32 expression with patient characteristics and survival. We also assessed TILs and their subsets (CD3⁺, CD4⁺, CD8⁺ and PD-1⁺) in the tumor nest. The level of RGC-32 expression was positively correlated with ISUP grade and Ki67 expression and was an independent poor prognosis factor of patients with ccRCC. RGC-32 expression was negatively correlated with the infiltration of TIL and CD3⁺T cells, but positively correlated with infiltration of PD-1⁺cells. In vitro studies showed that RGC-32 expression in renal cancer cells was downregulated by activated immune cells. Further investigation revealed that RGC-32 expression in renal cancer cells was inhibited by TNF-α and IL-1β secreted by activated immune cells. Collectively, these data indicate that RGC-32 could be a novel prognostic and druggable target related to the tumor-immune microenvironment in renal cancer.</p>","PeriodicalId":23244,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"102248"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"circICMT upregulates and suppresses the malignant behavior of bladder cancer.","authors":"Xin Luo, FangMei Xie, Guoqiang Qin, Ge Zou, Xu Lu, Chaofeng Zhang, Zeping Han, Ying Zhao, Xiaoyu Song, WenFeng Luo, Yongsheng Li, JinHua He, Jian Shen","doi":"10.1016/j.tranon.2024.102262","DOIUrl":"10.1016/j.tranon.2024.102262","url":null,"abstract":"<p><strong>Background: </strong>Circular RNA (circRNA) is a new type of endogenous single-stranded RNA with a covalently closed circular structure. Increasing evidence shows that circRNA plays an important role in regulating gene expression in tumors. circICMT is a circular RNA produced by the ICMT gene. Currently, the molecular function of circICMT in bladder cancer remains unclear.</p><p><strong>Method: </strong>Differentially expressed circRNAs were identified from RNA sequencing data and circICMT was identified as a new candidate circRNA. qRT-PCR and sanger sequencing were used to detect the expression of circICMT in bladder cancer tissue specimens. Stable cell lines overexpressing and knocking down circICMT were constructed to explore the effect of circICMT on bladder cancer cells. Its biological effects were detected through wound healing experiments, colony formation experiments, CCK-8 experiments and xenogeneic tumorigenesis experiments.</p><p><strong>Result: </strong>This study found that circICMT was significantly upregulated in bladder cancer tissue specimens. Overexpression of circICMT can inhibit cell migration, proliferation and colony formation ability, while knockdown of circICMT promotes the malignant phenotype of bladder cancer cells. Bioinformatics predictions have found that circICMT can bind to a variety of miRNAs and RBPs and may form a complex regulatory network to regulate the progression of bladder cancer.</p><p><strong>Conclusion: </strong>circICMT is significantly highly expressed in bladder cancer, and intervening circICMT expression affects the malignant phenotype of bladder cancer cells in vivo and in vitro, which may provide potential biomarkers and therapeutic targets for the management of bladder cancer.</p>","PeriodicalId":23244,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"102262"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A practical distribution pattern of α-SMA-positive carcinoma associated fibroblasts indicates poor prognosis of patients with pancreatic ductal adenocarcinoma.","authors":"Bo Li, Meilong Shi, Yang Wang, Penghao Li, Xiaoyi Yin, Guoxiao Zhang, Xiaochao Kang, Huan Wang, Suizhi Gao, Kailian Zheng, Xiaohan Shi, Xiongfei Xu, Yukun Zhou, Hui Jiang, Wei Jing, Shiwei Guo, Gang Jin","doi":"10.1016/j.tranon.2025.102282","DOIUrl":"10.1016/j.tranon.2025.102282","url":null,"abstract":"<p><p>Purpose The present study aimed to clarify the distribution pattern of carcinoma associated fibroblasts (CAFs) across pancreatic ductal adenocarcinoma (PDAC) and its prognostic prediction value. Methods Data of two cohorts were retrospectively collected from consecutive patients who underwent primary pancreatic resection from January 2015 to December 2017. We used tumor specimens to screen out the most suitable markers for the spatial distribution analysis for CAFs subpopulations. We utilized a tissue microarray to assess the spatial intensity of α-SMA expression within the tumor microenvironment. Specifically, we classified CAFs into two types based on their α-SMA spatial expression. Type II CAFs were designated as those located in the juxtatumoural stroma with α-SMA expression that was moderate or higher, and those in the peripheral stroma with α-SMA expression that was less than moderate. All other cases, where the α-SMA expression did not meet these criteria, were categorized as Type I CAFs. Multivariable Cox proportional hazards regression was used to assess risk factors associated with patient outcomes. RNA sequencing data were obtained from bulk tumor samples and isolated CAFs from patients to reveal the distinct pattern and elucidated their fundamental characteristics. Results The α-SMA spatial intensity was the most suitable variable for representative of CAFs spatial characteristics. Patients with Type Ⅰ CAFs were more likely to be allocated into N1 or N2 of the N stage and Ⅱ and Ⅲ of the TNM stage. The spatial distribution pattern of CAFs (Type Ⅰ v.s. Type Ⅱ: HR, 1.568; 95 % CI, 1.053-2.334; P = 0.027) was an independent prognostic factor in the discovery cohort, so as in the validation (Type Ⅰ vs. Type Ⅱ: HR, 2.197; 95 % CI, 1.410-3.422; P = 0.001). RNA sequencing analysis revealed that the differentially expressed genes (DEGs) in Type I CAFs are closely associated with those in corresponding tumor tissues, highlighting the enhanced biological significance of immune-related and oncogenic invasive pathways. Conclusions Our findings that two types of α-SMA-positive CAFs with different spatial patterns present heterogeneously across tissues of PDACs and correlated with patients' outcomes. The spatial location of CAFs may facilitate patients' selection in precision medicine of PDACs.</p>","PeriodicalId":23244,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"102282"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic significance of perioperative circulating CD56^bright NK cell and recovery of NK cell activity in patients with colorectal cancer undergoing radical surgery.","authors":"Jeng-Fu You, Cheng-Chi Lee, Yun-Shien Lee, Yih-Jong Chern, Chun-Kai Liao, Hung-Chih Hsu","doi":"10.1016/j.tranon.2024.102198","DOIUrl":"10.1016/j.tranon.2024.102198","url":null,"abstract":"<p><strong>Introduction: </strong>Natural killer (NK) cell activity (NKA) is downregulated in patients with colorectal cancer (CRC), and its dysfunction is possibly associated with increased risk of recurrence. However, its role in prognosis of CRC remains unclear. Prior research has shown that surgical stress can suppress NKA. This study explores the relationship between NK cell/NKA and clinicopathological factors during the perioperative period in patients with CRC.</p><p><strong>Methods: </strong>We prospectively enrolled 45 patients with CRC. Venous blood samples were collected preoperatively and on postoperative day 3 (POD3) and 30 (POD30). NKA was assessed by measuring the plasma levels of NK cell-secreted IFN-γ.</p><p><strong>Results: </strong>NKA was significantly reduced on POD3 compared with baseline levels before surgery but showed significant recovery by POD30. NKA on POD30 was considerably higher in patients with advanced disease stages or one or more high-risk preoperative factors. Additionally, a higher NKA recovery in patients with advanced stage exhibited improved recurrence-free survival (RFS) and progression-free survival (PFS) (hazards ratio (HR): 0.2442). Furthermore, an increased percentage of CD56^bright NK cells and a higher CD56^bright/CD56^dim NK cell ratio postoperatively on POD30 were associated with better RFS/PFS (HR: 0.2732, P = 0.0433 and HR: 0.2193, P = 0.024, respectively).</p><p><strong>Conclusions: </strong>Our findings indicate that a notable postoperative increase in CD56^bright NK cells on POD30, both in percentage and ratio, correlates with a more favorable prognosis in CRC patients. Additionally, higher recovery rates of NKA in patients with advanced stages may offer potential applications in risk stratification and the development of treatment strategies for CRC.</p>","PeriodicalId":23244,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"102198"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11683267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MRI-based deep learning and radiomics for predicting the efficacy of PD-1 inhibitor combined with induction chemotherapy in advanced nasopharyngeal carcinoma: A prospective cohort study.","authors":"Yiru Wang, Fuli Chen, Zhechen Ouyang, Siyi He, Xinling Qin, Xian Liang, Weimei Huang, Rensheng Wang, Kai Hu","doi":"10.1016/j.tranon.2024.102245","DOIUrl":"10.1016/j.tranon.2024.102245","url":null,"abstract":"<p><strong>Background: </strong>An increasing number of nasopharyngeal carcinoma (NPC) patients benefit from immunotherapy with chemotherapy as an induction treatment. Currently, there isn't a reliable method to assess the efficacy of this regimen, which hinders informed decision-making for follow-up care.</p><p><strong>Aim: </strong>To establish and evaluate a model for predicting the efficacy of programmed death-1 (PD-1) inhibitor combined with GP (gemcitabine and cisplatin) induction chemotherapy based on deep learning features (DLFs) and radiomic features.</p><p><strong>Methods: </strong>Ninety-nine patients diagnosed with advanced NPC were enrolled and randomly divided into training set and test set in a 7:3 ratio. From MRI scans, DLFs and conventional radiomic characteristics were recovered. The random forest algorithm was employed to identify the most valuable features. A prediction model was then created using these radiomic characteristics and DLFs to determine the effectiveness of PD-1 inhibitor combined with GP chemotherapy. The model's performance was assessed using Receiver Operating Characteristic (ROC) curve analysis, area under the curve (AUC), accuracy (ACC), and negative predictive value (NPV).</p><p><strong>Results: </strong>Twenty-one prediction models were constructed. The Tf_Radiomics+Resnet101 model, which combines radiomic features and DLFs, demonstrated the best performance. The model's AUC, ACC, and NPV values in the training and test sets were 0.936 (95%CI: 0.827-1.0), 0.9, and 0.923, respectively.</p><p><strong>Conclusion: </strong>The Tf_Radiomics+Resnet101 model, based on MRI and Resnet101 deep learning, shows a high ability to predict the clinically complete response (cCR) efficacy of PD-1 inhibitor combined with GP in advanced NPC. This model can significantly enhance the treatment management of patients with advanced NPC.</p>","PeriodicalId":23244,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"102245"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic prediction for inflammatory breast cancer patients using random survival forest modeling.","authors":"Yiwei Jia, Chaofan Li, Cong Feng, Shiyu Sun, Yifan Cai, Peizhuo Yao, Xinyu Wei, Zeyao Feng, Yanbin Liu, Wei Lv, Huizi Wu, Fei Wu, Lu Zhang, Shuqun Zhang, Xingcong Ma","doi":"10.1016/j.tranon.2024.102246","DOIUrl":"10.1016/j.tranon.2024.102246","url":null,"abstract":"<p><strong>Background: </strong>Inflammatory breast cancer (IBC) is an aggressive and rare phenotype of breast cancer, which has a poor prognosis. Thus, it is necessary to establish a novel predictive model of high accuracy for the prognosis of IBC patients.</p><p><strong>Methods: </strong>Clinical information of 1,230 IBC patients from 2010 to 2020 was extracted from the Surveillance, Epidemiology and End Results (SEER) database. Cox analysis was applied to identify clinicopathological characteristics associated with the overall survival (OS) of IBC patients. Random survival forest (RSF) algorithm was adopted to construct an accurate prognostic prediction model for IBC patients. Kaplan-Meier analysis was performed for survival analyses.</p><p><strong>Results: </strong>Race, N stage, M stage, molecular subtype, history of chemotherapy and surgery, and response to neoadjuvant therapy were identified as independent predictive factors for the OS of IBC patients. The top five significant variables included surgery, response to neoadjuvant therapy, chemotherapy, breast cancer molecular subtypes, and M stage. The C-index of RSF model was 0.7704 and the area under curve (AUC) values for 1, 3, 5 years in training and validation datasets were 0.879-0.955, suggesting the excellent predictive performance of RSF model. IBC patients were divided into high-risk group and low-risk group according the risk score of RSF model, and the OS of patients in the low-risk group was significantly longer than those in the high-risk group.</p><p><strong>Conclusion: </strong>In this study, we constructed a prognosis prediction model for IBC patients through RSF algorithm, which may potentially serve as a useful tool during clinical decision-making.</p>","PeriodicalId":23244,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"102246"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11713504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-Talk between NOK and EGFR: Juxtamembrane and Kinase domain interactions enhancing STAT3/5 signaling in breast cancer tumorigenesis.","authors":"Yinyin Wang, Bingdong Zhang, Chunhua He, Bo Tian, Sihan Liu, Jianghua Li, Jiayu Wang, Shigao Yang, Bingtao Zhu, Xiaoguang Wang, Zhijie Chang, Chenxi Cao","doi":"10.1016/j.tranon.2025.102276","DOIUrl":"10.1016/j.tranon.2025.102276","url":null,"abstract":"<p><p>Epidermal growth factor receptor (EGFR) plays an important role in the regulation of cell proliferation and migration [1]. It forms a homodimer or heterodimer with other ErbB receptor family members to activate downstream signaling. Emerging evidence indicates that the EGFR activity and downstream signaling are regulated by other proteins except its family members during tumorigenesis. Hence, investigating the diverse partnership profiles of EGFR is crucial for elucidating the mechanisms underlying EGFR-mediated actions in tumors, which in turn can guide the development of targeted therapeutic strategies. Here we report that NOK (also known as STYK1), a novel tyrosine kinase cross-talks with EGFR to promote tumorigenesis and metastasis of breast cancer cells. We found that NOK directly interacted with EGFR and formed a heterodimer complex in a manner of cross interaction via their juxtamembrane (JM) domains and kinase domains. Depletion of NOK impaired, but over-expression of NOK increased, the phosphorylation of EGFR. NOK enhanced EGF-induced phosphorylation of STAT3 and STAT5 via its juxtamembrane (JM) domain in promoting the proliferation and migration of breast cancer cells. Overexpression of NOK and EGFR synergistically induced the tumorigenesis of NIH-3T3 normal cells. We demonstrated that co-expression of NOK and EGFR correlated with tumor malignant stages in breast cancer patients. Our finding introduces a new cross interaction manner of EGFR-NOK via juxtamembrane (JM) domains and kinase domains, uncovers a mechanism by which NOK coordinates EGFR to enhance EGF-STAT3/5 signaling during tumorigenesis and metastasis, and proposes a potential strategy for targeting NOK-EGFR in breast cancer treatment.</p>","PeriodicalId":23244,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"102276"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modified CD15/CD16-CLL1 inhibitory CAR-T cells for mitigating granulocytopenia toxicities in the treatment of acute myeloid leukemia.","authors":"Rui Zhang, Yifan Zhao, Xiao Chai, Yingshuai Wang, Mohan Zhao, Shujing Guo, Yu Zhang, Mingfeng Zhao","doi":"10.1016/j.tranon.2024.102225","DOIUrl":"10.1016/j.tranon.2024.102225","url":null,"abstract":"<p><p>CLL1 Chimeric antigen receptor T-cell (CAR-T) therapy, as a promising immunotherapeutic approach, has demonstrated its potential to enhance the prognosis of patients diagnosed with acute myeloid leukemia (AML). However, due to the overexpression of CLL1 on neutrophils, CAR-T cells not only eliminated tumor cells but also eradicated neutrophils simultaneously, resulting in severe granulocytopenia and subsequent infections. Considering the distinct expression levels of CD15/CD16 on neutrophils and AML blasts, we have devised novel modified CD15 /CD16-CLL1 iCAR structures incorporating diverse inhibitory elements. Through extensive screening of structural optimization, we have successfully identified CD16-CLL1 iCAR-T cells that combine PD1 and 2B4 blockade, as well as a single VHH fragment replacing the entire CD16 scFv recognition domain. These modified cells demonstrate enhanced cytotoxicity against blasts while minimizing neutrophil elimination. Furthermore, their functionality has been effectively validated through both in vitro and in vivo experiments. In conclusion, we have successfully engineered innovative CD16-CLL1 iCAR-T cells, which preserves the cytotoxicity against tumor cells while preventing elimination of neutrophils, thereby significantly reducing the incidence of granulocytopenia during CAR-T therapy. Furthermore, our future objectives encompass the meticulous validation of both the efficacy and safety profile of this groundbreaking CAR-T therapy in clinical trials, as well as a comprehensive assessment of its potential to enhance the prognosis of patients diagnosed with AML.</p>","PeriodicalId":23244,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"102225"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysyl oxidase inhibitors in colorectal cancer progression.","authors":"Muxian Liu, Jie Wang, Meihong Liu","doi":"10.1016/j.tranon.2024.102233","DOIUrl":"10.1016/j.tranon.2024.102233","url":null,"abstract":"<p><p>The lysine oxidase (LOX) family, consisting of LOX and LOX-like-1-4 (LOXL1-LOXL4), catalyses the cross-linking reaction of collagen and elastin in the extracellular matrix (ECM). Numerous studies have demonstrated that LOX family members are dysregulated in a variety of cancers, including colorectal cancer (CRC), and play a key role in cancer cell migration, proliferation, invasion and metastasis. Targeting LOX family proteins with specific inhibitors has therefore been developed as a new therapeutic strategy for cancer. In this paper, we review the role of LOX enzymes in the development and progression of CRC. In addition, we address recent advances in the development of LOX/LOXL inhibitors, highlighting the potential use of this inhibitor as an effective and complementary treatment for CRC.</p>","PeriodicalId":23244,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"102233"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11713484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP-deleted cancers.","authors":"Kimberly J Briggs, Kevin M Cottrell, Matthew R Tonini, Alice Tsai, Minjie Zhang, Douglas A Whittington, Wenhai Zhang, Steven A Lombardo, Satoshi Yoda, Erik W Wilker, Samuel R Meier, Yi Yu, Teng Teng, Alan Huang, John P Maxwell","doi":"10.1016/j.tranon.2024.102264","DOIUrl":"10.1016/j.tranon.2024.102264","url":null,"abstract":"<p><p>TNG908 is a clinical stage PRMT5 inhibitor with an MTA-cooperative binding mechanism designed to leverage the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. MTAP deletion occurs in 10-15 % of all human cancer representing multiple histologies. MTA is a negative regulator of PRMT5 that accumulates as a result of MTAP deletion. In this study, we demonstrate that TNG908 selectively binds the PRMT5·MTA complex driving selective inhibition of PRMT5 in MTAP-null cancers, a mechanism that creates a large therapeutic index relative to first generation PRMT5 inhibitors that have alternative binding mechanisms that are not tumor-selective. Strong preclinical activity in multiple MTAP-deleted xenograft models, as well as demonstrated brain penetrance in preclinical models, support the potential for histology-agnostic clinical development of TNG908 in MTAP-deleted solid tumors, including CNS malignancies. TNG908 is being tested clinically in patients with MTAP-deleted tumors, including glioblastoma, in a Phase I/II clinical trial (NCT05275478).</p>","PeriodicalId":23244,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"102264"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}