{"title":"Targeting MAN1B1 potently enhances bladder cancer antitumor immunity via deglycosylation of CD47","authors":"Jie Zhang, Chen Zhang, Ruichen Zang, Weiwu Chen, Yining Guo, Haofei Jiang, Jing Le, Kunyu Wang, Haobo Fan, Xudong Wang, Sisi Mo, Peng Gao, Wenhao Guo, Xinrong Jiang, Fengbin Gao, Junming Jiang, Juyan Zheng, Yuxing Chen, Yicheng Chen, Yanlan Yu, Guoqing Ding","doi":"10.1002/cac2.70040","DOIUrl":"10.1002/cac2.70040","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Only a few bladder cancer patients benefit from anti-programmed cell death protein 1/programmed cell death ligand 1 immunotherapy. The cluster of differentiation 47 (CD47) plays an important role in tumor immune evasion. CD47 is a highly glycosylated protein, however, the mechanisms governing CD47 glycosylation and its potential role in immunosuppression are unclear. Therefore, this study aimed to evaluate the function of CD47 glycosylation in bladder cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Western blotting, immunohistochemistry, and flow cytometry were used to measure protein expression, protein-protein interactions, and phagocytosis in bladder cancer. A murine model was employed to investigate the impact of mannosidase alpha class 1B member 1 (MAN1B1) modification of CD47 on anti-phagocytosis in vivo. An <i>ex vivo</i> model, patient-derived tumor-like cell clusters, was used to examine the effect of targeting MAN1B1 on phagocytosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our research identified that aberrant CD47 glycosylation was responsible for its immunosuppression. The glycosyltransferase MAN1B1 responsible for CD47 glycosylation was highly expressed in bladder cancer. Abnormal activation of extracellular signal-regulated kinase (ERK) was significantly associated with MAN1B1 stability by regulating the interaction between MAN1B1 and the E3 ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1). Mechanistically, abnormally activated ERK stabilized MAN1B1, resulting in the glycosylation of CD47 and facilitating immune evasion by enhancing its interaction with signal-regulatory protein alpha (SIRP-α). In vitro and in vivo experiments demonstrated that <i>MAN1B1</i> knockout weakened CD47-mediated anti-phagocytosis. MAN1B1 inhibitors promoted phagocytosis without causing anemia, offering a safe alternative to anti-CD47 therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This comprehensive analysis uncovered that ERK activation stabilizes MAN1B1 by regulating the interaction between MAN1B1 and HRD1, facilitates immune evasion via CD47 glycosylation, and presents new potential targets and strategies for cancer immunotherapy that do not cause anemia.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 9","pages":"1090-1112"},"PeriodicalIF":24.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Adjuvant capecitabine in combination with docetaxel and cyclophosphamide versus anthracycline plus docetaxel and cyclophosphamide regimen in women with high-risk, HER2-negative breast cancer: An open-label, randomized controlled trial","authors":"Yu Song, Yingjiao Wang, Xi Cao, Ying Xu, Yidong Zhou, Qiang Sun, Songjie Shen","doi":"10.1002/cac2.70041","DOIUrl":"10.1002/cac2.70041","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The standard adjuvant chemotherapy for early-stage, high-risk breast cancer includes anthracyclines and taxanes. While anthracycline-based regimens have proven effective in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, their efficacy may be reduced in HER2-negative patients due to the lack of co-amplification of DNA topoisomerase IIα, the primary target of anthracyclines. This study compared the efficacy and safety of the regimen of docetaxel, anthracycline, and cyclophosphamide (TAC) versus a novel regimen consisting of docetaxel, cyclophosphamide, and capecitabine (TCX), hypothesizing that replacement of anthracycline with capecitabine could offer superior outcomes in this patient population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this open-label, randomized controlled trial, 204 patients with pT1-3, node-positive or high-risk node-negative, HER2-negative early-stage breast cancer were enrolled between May 2011 and December 2013 (ClinicalTrials.gov: NCT01354522). Patients were randomized 2:1 to TAC (<i>n</i> = 136) or TCX (<i>n</i> = 68), with treatment administered every 21 days for six cycles. The primary endpoints were disease-free survival (DFS) and overall survival (OS); secondary endpoints included distant disease-free survival (DDFS), disease-specific survival (DSS), and adverse event (AE) rates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>With a median follow-up of 124.4 (range, 19.5-147.8) months, TCX did not significantly improve the 10-year DFS rate over TAC (71.5% ± 5.6% vs. 67.6% ± 4.0%, <i>P</i> = 0.477). However, the 10-year OS rate was significantly higher in the TCX group than in the TAC group (91.0% ± 3.5% vs. 77.2% ± 3.6%, <i>P =</i> 0.009). The TCX group also showed trends toward improved 10-year DDFS rate (82.0% ± 4.7% vs. 69.8% ± 3.9%, <i>P =</i> 0.052) and significantly higher 10-year DSS rate (93.9% ± 3.0% vs. 77.8% ± 3.6%, <i>P =</i> 0.002) compared to the TAC group. Grade 3-4 AEs occurred significantly more often in the TAC group than the TCX group (67.7% vs. 42.7%, <i>P</i> = 0.001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>TCX may provide superior long-term survival and a more favorable safety profile compared to TAC for patients with high-risk HER2-negative breast cancer, warranting further investigation in larger cohorts.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 9","pages":"1113-1122"},"PeriodicalIF":24.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Seonghye Kim, Bongseong Kim, Kyu-won Jung, Ga Eun Nam, Wonyoung Jung, Junhee Park, Kyung-Do Han, Dong Wook Shin
{"title":"Associations of body mass index and waist circumference with incidence of overall and of 27 site-specific cancers: a population-based retrospective cohort study","authors":"Seonghye Kim, Bongseong Kim, Kyu-won Jung, Ga Eun Nam, Wonyoung Jung, Junhee Park, Kyung-Do Han, Dong Wook Shin","doi":"10.1002/cac2.70039","DOIUrl":"10.1002/cac2.70039","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Overweight and obesity are known risk factors for cancer. The aim of this study was to investigate associations of body mass index (BMI) and waist circumference (WC) with incidence of 27 site-specific cancers stratified by sex and menopausal status accounting for non-linearity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a population-based retrospective cohort study using the Korean National Health Insurance Service (KNHIS 2009-2020) database. We included 3,986,155 participants (aged ≥ 20 years), and the mean follow-up duration was 9.0 ± 1.6 years. The primary outcome was the incidence of cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>There were positive associations between BMI or WC and incidences of cancers including overall cancer, digestive tract cancer (except for esophageal cancer), hepato-bilio-pancreatic cancer, hematological cancer, sex-specific cancers, brain/central nervous system (postmenopausal women), thyroid, renal, and bladder cancers. We observed inverse associations for several cancers, including lung and laryngeal cancers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings of differential associations of BMI and WC with incidence of various cancers contribute to the understanding of the relationship between obesity and cancer risk in Asian populations. These results may provide evidence to support the implementation of active surveillance and targeted management strategies for obesity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 9","pages":"1075-1089"},"PeriodicalIF":24.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mengyi Lao, Xiaozhen Zhang, Zejun Li, Kang Sun, Hanshen Yang, Sicheng Wang, Lihong He, Yan Chen, Hanjia Zhang, Jiatao Shi, Daqian Xu, Tingbo Liang, Xueli Bai
{"title":"Lipid metabolism reprograming by SREBP1-PCSK9 targeting sensitizes pancreatic cancer to immunochemotherapy","authors":"Mengyi Lao, Xiaozhen Zhang, Zejun Li, Kang Sun, Hanshen Yang, Sicheng Wang, Lihong He, Yan Chen, Hanjia Zhang, Jiatao Shi, Daqian Xu, Tingbo Liang, Xueli Bai","doi":"10.1002/cac2.70038","DOIUrl":"10.1002/cac2.70038","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pancreatic cancer's aberrant lipid metabolism fuels cell growth, invasion, and metastasis, yet its impact on immune surveillance and immunotherapy is unclear. This study investigated how sterol regulatory element-binding transcription factor 1 (SREBP1)-driven lipid metabolism affects the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Clinical significance of SREBP1 was assessed in a PDAC cohort from China and The Cancer Genome Atlas (TCGA) cohorts. The in vitro mechanisms that SREBP1 regulated programmed cell death-ligand 1 (PD-L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9) were investigated using immunofluorescence, flow cytometry, Western blotting, luciferase assays and chromatin immunoprecipitation. In vivo studies using PDAC-bearing mice, humanized patient-derived tumor xenograft (PDX) models, and autochthonous model of mutation (GEMM-KTC) evaluated the efficacy and mechanisms of programmed death receptor 1 (PD-1) antibodies and lipid inhibitors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Patients responding to anti-PD-1 therapy exhibited lower serum lipid levels than non-responders. Targeting SREBP1 disrupted lipid metabolism, decelerated tumor growth, and boosted the efficacy of immunotherapy for PDAC. Mechanistically, SREBP1 directly bound the PD-L1 promoter, suppressing its transcription. Meanwhile, PCSK9, a direct transcriptional target of SREBP1, modulated PD-L1 levels via lysosomal degradation. Consequently, the combination of PCSK9-neutralizing antibodies with PD-1 monotherapy showed a robust antitumor effect in both humanized PDX and GEMM-KTC models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The SREBP1-PCSK9 axis-mediated lipid metabolism is crucial for triggering immune evasion and resistance to anti-PD-1. Targeting the SREBP1-PCSK9 axis could potentially reverse PDAC's resistance to anti-PD-1 therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"1010-1037"},"PeriodicalIF":24.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jinghan Zhu, Yixiao Xiong, Yuxin Zhang, Huifang Liang, Kun Cheng, Yuanxiang Lu, Guangzhen Cai, Yang Wu, Yunhui Fan, Xiaoping Chen, Hong Zhu, Zeyang Ding, Wanguang Zhang
{"title":"Simvastatin overcomes the pPCK1-pLDHA-SPRINGlac axis-mediated ferroptosis and chemo-immunotherapy resistance in AKT-hyperactivated intrahepatic cholangiocarcinoma","authors":"Jinghan Zhu, Yixiao Xiong, Yuxin Zhang, Huifang Liang, Kun Cheng, Yuanxiang Lu, Guangzhen Cai, Yang Wu, Yunhui Fan, Xiaoping Chen, Hong Zhu, Zeyang Ding, Wanguang Zhang","doi":"10.1002/cac2.70036","DOIUrl":"10.1002/cac2.70036","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Intrahepatic cholangiocarcinoma (ICC) is a challenging cancer with an increasing incidence. The Phase III TOPAZ-1/KEYNOTE-966 study demonstrated chemo-immunotherapy (CIT) as a significant advancement, potentially replacing traditional chemotherapy for advanced biliary tract cancer. Ferroptosis is a crucial process that affects cancer cell survival and therapy resistance. Although AKT hyperactivation is prevalent in numerous cancers, including ICC, its role in ferroptosis resistance remains unclear. This study explored whether targeting ferroptosis can enhance CIT response rates, specifically in ICC patients with AKT hyperactivation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In vivo metabolic CRISPR screening in a Kras<sup>G12D</sup>/Tp53<sup>−/−</sup> ICC mouse model was used to identify primary regulators of ferroptosis during CIT (gemcitabine, cisplatin, and anti-mouse programmed cell death 1 ligand 1). Phosphoenolpyruvate carboxykinase 1 (PCK1) was assessed for its role in ferroptosis and treatment resistance in preclinical models under AKT activation levels. Molecular and biochemical techniques were used to explore PCK1-related resistance mechanisms in AKT-hyperactivated ICC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Under AKT hyperactivation condition, phosphorylated PCK1 (pPCK1) promoted metabolic reprogramming, enhancing ubiquinol and menaquinone-4 synthesis through the mevalonate (MVA) pathway. This cascade was mediated by the pPCK1-pLDHA-SPRINGlac axis. Inhibiting PCK1 phosphorylation or using simvastatin significantly augmented CIT efficacy in preclinical models. Clinical data further indicated that phosphorylated AKT (pAKT)-pPCK1 levels might serve as a biomarker to predict CIT response in ICC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study identified the pAKT-pPCK1-pLDHA-SPRINGlac axis as a novel mechanism driving ferroptosis resistance in AKT-hyperactivated ICC by associating glycolytic activation with MVA flux reprogramming. Targeting this axis, potentially through statin-based therapies, may offer a strategy to sensitize ICC cells to ferroptosis and improve treatment outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"1038-1071"},"PeriodicalIF":24.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ying Cheng, Shuang Zhang, Liang Han, Lin Wu, Jun Chen, Peiyan Zhao, Hongmei Sun, Guilan Wen, Yinghua Ji, Anastasia Zimina, Jianhua Shi, Zhijie Pan, Jinsheng Shi, Xicheng Wang, Yuansong Bai, Tamar Melkadze, Yueyin Pan, Xuhong Min, Maksym Viguro, Xingya Li, Yanqiu Zhao, Junquan Yang, Tamta Makharadze, Ekaterine Arkania, Haoyu Yu, Jing Li, Fang Yang, Xinyi Yang, Chen Ling, Qingyu Wang, Yongqiang Shan, Jun Zhu, the ASTRUM-005 Study Group
{"title":"First-line serplulimab plus chemotherapy in extensive-stage small-cell lung cancer: Updated results and biomarker analysis from the ASTRUM-005 randomized clinical trial","authors":"Ying Cheng, Shuang Zhang, Liang Han, Lin Wu, Jun Chen, Peiyan Zhao, Hongmei Sun, Guilan Wen, Yinghua Ji, Anastasia Zimina, Jianhua Shi, Zhijie Pan, Jinsheng Shi, Xicheng Wang, Yuansong Bai, Tamar Melkadze, Yueyin Pan, Xuhong Min, Maksym Viguro, Xingya Li, Yanqiu Zhao, Junquan Yang, Tamta Makharadze, Ekaterine Arkania, Haoyu Yu, Jing Li, Fang Yang, Xinyi Yang, Chen Ling, Qingyu Wang, Yongqiang Shan, Jun Zhu, the ASTRUM-005 Study Group","doi":"10.1002/cac2.70032","DOIUrl":"10.1002/cac2.70032","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The ASTRUM-005 study previously demonstrated a significant overall survival (OS) benefit with serplulimab (a programmed death 1 inhibitor) plus chemotherapy versus chemotherapy alone in previously untreated extensive-stage small-cell lung cancer (ES-SCLC). Here, we report updated efficacy and safety results after an extended median follow-up of 19.8 months, along with the first report on findings from exploratory biomarker analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 585 patients were randomized in a 2:1 ratio to receive 4.5 mg/kg serplulimab (<i>n</i> = 389) or placebo (<i>n</i> = 196) intravenously every 3 weeks, together with carboplatin and etoposide. The primary endpoint was OS. In addition, genomic profiling was performed to identify mutated genes, and quantitative serum proteome profiling was conducted to identify differentially expressed proteins (DEPs) between responders and non-responders of serplulimab plus chemotherapy. Regression analysis was subsequently used to construct a protein signature based on the DEPs. The associations between efficacy outcomes (objective response rate [ORR], OS, and progression-free survival [PFS]) and gene mutation status or DEP expression were also examined with regression analysis. Furthermore, the prognostic value of hematological parameters was evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the intent-to-treat population, the median OS was 15.8 months in the serplulimab group versus 11.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval, 0.50-0.76; <i>P</i> < 0.001). We identified 181 DEPs between responders and non-responders in the serplulimab group, from which a 15-protein signature was constructed. In the serplulimab group, patients with a higher 15-protein signature score were associated with significantly longer OS and PFS. Also, patients harboring tumor-suppressor retinoblastoma-1 (<i>RB1</i>) mutations or mutations in Notch pathway members showed improved ORR, OS, or PFS compared with their wild-type counterparts. Baseline neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) level were independent prognosticators of patients with ES-SCLC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>First-line serplulimab provided a sustained clinical benefit over placebo in patients with ES-SCLC. A 15-protein signature and mutations in <i>RB1</i> or Notch pathway genes may serve as predictive biomarkers for benefits from serplulimab plus chemotherapy, while baseline NLR and LDH were independe","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"990-1009"},"PeriodicalIF":24.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cell-free DNA blood-based test compared to fecal immunochemical test for colorectal cancer screening","authors":"Teresa Seum, Michael Hoffmeister, Hermann Brenner","doi":"10.1002/cac2.70037","DOIUrl":"10.1002/cac2.70037","url":null,"abstract":"<p>Screening for colorectal cancer (CRC) is among the most effective approaches to cancer prevention, yet achieving high adherence to effective screening offers is challenging [<span>1</span>]. Blood-based tests that could be easily implemented in routine medical practice might be a promising approach to achieve higher adherence rates than with conventional stool-based or endoscopic screening [<span>2, 3</span>]. However, neoplasm detection rates of previously developed and proposed blood-based tests have not been competitive to those of modern stool-based tests [<span>2</span>], in particular fecal immunochemical tests (FITs) that are meanwhile widely used for CRC screening in an increasing number of countries [<span>4</span>]. Most recently, performance of a novel cell-free DNA (cfDNA) blood-based test for detecting colorectal neoplasms was validated in the ECLIPSE study, a large screening population undergoing screening colonoscopy [<span>5</span>], being the first of its kind to achieve FDA approval as a primary screening option for CRC.</p><p>Although detailed results on sensitivity and specificity were reported, the ECLIPSE study [<span>5</span>] did not include comparative results for screening by FIT, the best established and most widely used noninvasive CRC screening test. We aimed to compare reported measures of diagnostic performance of the cfDNA blood-based test to those of a commercially available FIT (FOB Gold, Sentinel Diagnostics, cutoff 17.0 µg hemoglobin per gram feces) in the BLITZ study, a comparable large cohort of screening colonoscopy participants recruited in the context of the German screening colonoscopy program. The complete description of the methods can be found in the Supplementary Materials and Methods.</p><p>In order to match the inclusion and exclusion criteria of the ECLIPSE study as closely as possible, analogous exclusion criteria were applied to the BLITZ sample, resulting in 5,683 participants from the BLITZ study to be included in the analysis (Supplementary Figure S1).</p><p>Supplementary Table S1 summarizes the characteristics of the ECLIPSE study, conducted in the United States with 7,861 screening colonoscopy participants, and the selected study sample from the BLITZ study. Mean age and sex distributions of participants in the ECLIPSE study (60.3 years, 53.7% women) and the BLITZ study (61.2 years, 50.4% women) were similar, as were the proportions of participants in whom CRC was detected (0.8% in both studies). Advanced precancerous lesions (APCLs) were somewhat more commonly found in the ECLIPSE study (14.2% vs. 10.3%) (Supplementary Table S1).</p><p>In the ECLIPSE study, 11.4% of participants were tested positive by the cfDNA blood test, while 9.9% tested positive by the FIT in the BLITZ study (Table 1). Applying the FIT manufacturer's recommended cutoff, the sensitivity of FIT was much higher than the cfDNA test in detecting APCL (31.5% vs. 13.2%, <i>P</i> < 0.001) and showed an approximately one ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"987-989"},"PeriodicalIF":24.9,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Young Kwang Chae, Megan Othus, Sandip Pravin Patel, Raid Aljumaily, Khine Z. Win, Tanya Pejovic, Sajeve S. Thomas, William R. Robinson III, Hye Sung Kim, Liam Il-Young Chung, Christine M. McLeod, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock
{"title":"A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: durable responses and delayed pseudoprogression in small cell carcinoma of the ovary, hypercalcemic type cohort","authors":"Young Kwang Chae, Megan Othus, Sandip Pravin Patel, Raid Aljumaily, Khine Z. Win, Tanya Pejovic, Sajeve S. Thomas, William R. Robinson III, Hye Sung Kim, Liam Il-Young Chung, Christine M. McLeod, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock","doi":"10.1002/cac2.70020","DOIUrl":"10.1002/cac2.70020","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The combined use of anti-programmed cell death protein 1 (<i>PD-1</i>)/anti-cytotoxic T-lymphocyte associated protein 4 (<i>CTLA-4)</i> checkpoint inhibitors has been effective in various cancer types. The Southwest Oncology Group (SWOG) Dual Anti-<i>CTLA-4</i> and Anti-<i>PD-1</i> Blockade in Rare Tumors (DART) S1609 study investigated ipilimumab and nivolumab in ultra-rare cancers, including small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The purpose of the study was to evaluate the potential clinical benefit of ipilimumab and nivolumab in patients with SCCOHT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>DART was a prospective, open-labeled, multicenter (>1,000 US sites), multi-cohort phase II clinical trial of intravenous administration of ipilimumab (1 mg/kg, every 6 weeks) plus nivolumab (240 mg, every 2 weeks). The primary endpoint was overall response rate [ORR, confirmed complete response (CR) and partial response (PR)] per RECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; overall response plus stable disease ≥6 months), and toxicity. Immune responses were also evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Six patients (median age, 30.5 years; median, 2 prior therapies; no prior immunotherapy exposure) with advanced/metastatic SCCOHT were evaluable. ORR and CBR were both 16.7% (1/6) with one patient having a confirmed CR lasting 46.2+ months. However, another patient had a confirmed immune CR (iCR) with immune PFS (iPFS) of 53+ months [ORR/iORR, 33.3% (2/6)]. Notably, the latter patient had a progressing lesion at 24 weeks after initial response, but with renewed regression with ongoing therapy, suggesting delayed pseudo-progression. At 12-months, 3 patients remained alive. Median PFS was 1.4 months (range, 0.9 months-not reached); median OS was 14.2 months (2 months-not reached). No adverse events caused treatment discontinuation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Two of 6 patients (33.3%) with SCCOHT achieved durable CR/iCR and long-term survival with ipilimumab plus nivolumab. Correlative studies to determine response and resistance markers are ongoing.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"976-986"},"PeriodicalIF":24.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Monika Raab, Balázs Győrffy, Samuel Peña-Llopis, Daniela Fietz, Monika Kressin, Margareta Kolaric, Matthias Ebert, Khayal Gasimli, Sven Becker, Mourad Sanhaji, Klaus Strebhardt
{"title":"Targeted reactivation of the novel tumor suppressor DAPK1, an upstream regulator of p53, in high-grade serous ovarian cancer by mRNA liposomes reduces viability and enhances drug sensitivity in preclinical models","authors":"Monika Raab, Balázs Győrffy, Samuel Peña-Llopis, Daniela Fietz, Monika Kressin, Margareta Kolaric, Matthias Ebert, Khayal Gasimli, Sven Becker, Mourad Sanhaji, Klaus Strebhardt","doi":"10.1002/cac2.70029","DOIUrl":"10.1002/cac2.70029","url":null,"abstract":"<p>Ovarian cancer, particularly high-grade serous ovarian cancer (HGSOC), remains the most lethal gynecological malignancy, with a 5-year survival rate of around 40% due to late diagnosis, recurrence, and the development of chemoresistance [<span>1, 2</span>]. Mutations in tumor protein 53 (<i>TP53</i>) occur in over 96% of HGSOC cases, impairing its tumor-suppressive functions, including cell cycle control, DNA repair, and apoptosis. Mutant <i>TP53</i> promotes tumor progression, genomic instability, and resistance to standard therapies, thereby worsening patient outcomes [<span>3, 4</span>]. Death-associated protein kinase 1 (<i>DAPK1</i>) is a key regulator of apoptosis and autophagy [<span>5, 6</span>]. While p53 can upregulate <i>DAPK1</i> expression, DAPK1 in turn stabilizes p53 by inhibiting its negative regulator, murine double minute 2 (MDM2). This reciprocal regulation forms a feedback loop that reinforces p53's tumor-suppressive function. We identified aberrant DAPK1 expression in ovarian cancer and sought to investigate whether restoring DAPK1 function could serve as a potential therapeutic strategy. Recent advancements in mRNA-based therapies offer a promising approach to gene restoration. Thus, we investigated whether in vitro-transcribed (IVT)-mRNA encoding DAPK1 could serve as an effective therapeutic strategy for HGSOC. Here, we explore the potential of mRNA-based reactivation of DAPK1 to regulate cell survival and apoptosis in HGSOC.</p><p>In studies using mammalian vectors to deliver functional proteins for replacement therapy, reducing the length of recombinant DNA vectors has been shown to enhance transfection efficiency, translation, and persistence in cells [<span>7-9</span>]. Given the relatively long open reading frame of <i>DAPK1</i> (4,290 base pairs), we generated a series of constructs containing different functional domains of DAPK1 and assessed their anti-tumor efficacy in ovarian cancer cells. We found that a truncated <i>DAPK1</i> variant, containing the kinase domain, ankyrin repeats, and death domain (KD-AR-DD), retained potent tumor-suppressive activity despite being approximately 50% shorter than the wild-type protein. Compared to other truncated constructs, mammalian vector-based expression of KD-AR-DD strongly activated Caspase-3/7 and significantly sensitized OVCAR-3 cells to paclitaxel treatment (Supplementary Figure S1A-C). Based on these findings, we selected KD-AR-DD as the basis for designing an IVT-mRNA construct, referred to as ∆DAPK1-mRNA (Figure 1A), optimized to induce cell death in ovarian cancer cells. For IVT-mRNA synthesis, we employed a bacterial vector containing a T7 RNA polymerase promoter to drive transcription of human truncated <i>DAPK1</i>, focusing on optimizing translational efficacy and mRNA stability [<span>9</span>]. To deliver ∆DAPK1-mRNA to HGSOC cells, we utilized a liposomal system with Lipofectamine MessengerMAX Transfection Reagent. Treatment of OVCAR-8 cells with increasing","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"966-970"},"PeriodicalIF":24.9,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Edmund Chiong, Ziteng Wang, Eleanor Jing Yi Cheong, Yi Chen Yao, Sin Mun Tham, Revathi Periaswami, Poh Choo Toh, Ziting Wang, Qing Hui Wu, Woon Chau Tsang, Arshvin Kesavan, Alvin Seng Cheong Wong, Patrick Thomas Wong, Felicia Lim, Shuaibing Liu, Eric Chun Yong Chan
{"title":"Evaluation of exposure-response-safety relationship of model-informed low-dose 500 mg abiraterone acetate in prostate cancer patients","authors":"Edmund Chiong, Ziteng Wang, Eleanor Jing Yi Cheong, Yi Chen Yao, Sin Mun Tham, Revathi Periaswami, Poh Choo Toh, Ziting Wang, Qing Hui Wu, Woon Chau Tsang, Arshvin Kesavan, Alvin Seng Cheong Wong, Patrick Thomas Wong, Felicia Lim, Shuaibing Liu, Eric Chun Yong Chan","doi":"10.1002/cac2.70035","DOIUrl":"10.1002/cac2.70035","url":null,"abstract":"<p>Prostate cancer is a common cancer among men worldwide. Large-scale clinical studies of the 1,000 mg daily dosing of abiraterone acetate (AA) have confirmed its antitumor efficacy in patients with metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC), regardless of their cancer's response to androgen deprivation therapy (ADT) or treatment duration. However, this dosage was indirectly justified based on the absence of dose-limiting toxicities (DLTs) in prior phase I dose-escalation trials, where a plateau in the increase of upstream steroids relating to secondary mineralocorticoid excess was observed at doses greater than 750 mg and up to 2,000 mg daily [<span>1, 2</span>]. Notably, prostate specific antigen (PSA) levels declined at all investigated doses (250 to 1,000 mg) [<span>1, 2</span>].</p><p>Cytochrome P450 17A1 (CYP17A1) is involved in both adrenal and de novo intratumoural androgen biosynthesis. We previously identified that abiraterone targeted CYP17A1 via a two-step binding mechanism [<span>3</span>]. Our subsequent pharmacokinetic/pharmacodynamic (PK/PD) simulations found that both the 1,000 mg and 500 mg doses of AA achieved comparable > 80% apparent target CYP17A1 enzyme occupancy and equipotent reduction of downstream plasma dehydroepiandrostenedione-sulfate (DHEA-S) levels, despite the difference in systemic exposure of abiraterone [<span>3</span>]. In addition, we developed physiologically-based pharmacokinetic (PBPK) models for AA and abiraterone via a middle-out approach [<span>4</span>], which enabled the prospective prediction of abiraterone systemic exposure at different doses.</p><p>Our research group participated in a global phase II study that demonstrated a 250 mg dose of AA taken with a low-fat meal achieved comparable PSA metrics to the standard 1,000 mg AA dose taken in a fasting state in patients with CRPC [<span>5</span>]. However, the fat content of food could significantly impact the relative bioavailability of abiraterone [<span>4</span>], and controlling food intake poses a challenge in outpatient settings and during the long-term use of abiraterone. By analyzing the PK data, we observed that the systemic exposure of a lower dose of 500 mg of AA (fasted) is comparable to that of a 250 mg dose of AA with a low-fat meal. Furthermore, our modeling studies revealed that 500 mg AA is promising in achieving optimal antitumor efficacy, and diminishing mineralocorticoid-related adverse outcomes simultaneously. In addition, patients will pay less with a half-reduced dose. Currently, data on the administration of 500 mg AA in prostate cancer patients remains insufficient. To address this gap, we conducted a proof-of-concept phase I study in mCRPC and mHSPC patients newly initiated on 500 mg once daily AA. Simultaneous PBPK/PD simulations of the low-dose AA were performed to further support the unique relationship between systemic exposure and pharmacological ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"971-975"},"PeriodicalIF":24.9,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}