Cancer Science最新文献

{"title":"KRAB Zinc-Finger Protein ZNF205 Promotes Hepatocellular Carcinoma via p53 Pathway Repression","authors":"Xiaofen Huang,&nbsp;Yingchuan Yang,&nbsp;Yuan Ma,&nbsp;Wei Hao,&nbsp;Jingzhuo Jin,&nbsp;Yue Ding,&nbsp;Yiming Zhang,&nbsp;Xiuyuan Zhang,&nbsp;Xinli Li,&nbsp;Qin Song,&nbsp;Jiaqi Liu,&nbsp;Bingxin Liu,&nbsp;Yuanjun Zhai,&nbsp;Chunling Zhao,&nbsp;Jin Wu,&nbsp;Chunyan Tian","doi":"10.1111/cas.70337","DOIUrl":"10.1111/cas.70337","url":null,"abstract":"<p>The tumor suppressor p53 is frequently dysregulated in cancer, whereas the mechanisms underlying its functional impairment remain unclear. Our previously identified KRAB domain-containing zinc finger proteins (KZFPs) as key p53 regulators in tumorigenesis and progression, specific members and their cancer-relevant mechanistic roles require further characterization. Here, we identified ZNF205, an SQ/TQ motif-bearing KZFP, as a critical oncogenic regulator in HCC. The pan-cancer analysis related to revealed that ZNF205 is an unfavorable prognostic factor for p53 wild-type patients with hepatocellular carcinoma (HCC). ZNF205 interacts with p53 and significantly inhibits its transcriptional activity by impeding the binding of p53 to target genes. Overexpression and knockdown of ZNF205 increase and decrease the malignant phenotype of HCC cells in a p53-dependent manner both in vitro and in vivo, respectively. Our study unveils ZNF205 as a novel p53 regulator and establishes its pro-tumorigenic function in HCC. These results reveal a novel p53 dysregulation mechanism in HCC and expand known KZFP-mediated p53 inactivation pathways, nominating ZNF205 as a therapeutic target to restore p53 function in HCC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 4","pages":"1057-1071"},"PeriodicalIF":4.3,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158910","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":"Development and Validation of a Urinary Exosomal miRNA Diagnostic Panel for Early Detection of Esophageal Cancer","authors":"Tatsuro Murano,&nbsp;Hiroki Yamashita,&nbsp;Yuki Kano,&nbsp;Ken Takeuchi,&nbsp;Takayuki Amano,&nbsp;Takanobu Yoshimoto,&nbsp;Mayuko Otomo,&nbsp;Hisashi Fujiwara,&nbsp;Shin Namiki,&nbsp;Hiroki Yamaguchi,&nbsp;Yoriko Ando,&nbsp;Yumi Nishiyama,&nbsp;Mika Mizunuma,&nbsp;Yuki Ichikawa,&nbsp;Tomonori Yano","doi":"10.1111/cas.70298","DOIUrl":"10.1111/cas.70298","url":null,"abstract":"<p>Esophageal squamous cell carcinoma (ESCC) remains a leading cause of cancer-related mortality, with early detection being challenging. Although endoscopic screening can aid in diagnosis, its invasiveness and cost limit widespread compliance. To address this, we developed and validated a non-invasive diagnostic panel based on urinary exosomal microRNAs (miRNAs) for early ESCC detection. Urine samples were prospectively collected from ESCC patients and healthy controls across five institutions, and exosomal miRNA profiles were obtained using small RNA sequencing. A diagnostic panel was constructed using machine learning with recursive feature elimination in a proof-of-concept (POC) cohort comprising 99 ESCC and 93 control samples, and its performance was evaluated by five-fold cross-validation. This panel was subsequently tested in a blinded validation cohort of 50 ESCC and 61 control samples. In the POC cohort, the multi-miRNA panel achieved an area under the curve (AUC) of 0.90. In the validation cohort, the AUC was 0.85 (95% CI: 0.77–0.92), with 84% sensitivity and 66% specificity. The panel showed high sensitivity across disease stages—100% for Stage 0, 91% for Stage I, and 73% for Stages II–IV—and its performance was not significantly affected by sex, body mass index, alcohol use, or smoking. Furthermore, in early-stage cases, the diagnostic score significantly declined after treatment (<i>p</i> = 0.026). These findings suggest that the urinary exosomal miRNA panel may offer a practical screening approach for the early detection of ESCC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 4","pages":"1080-1092"},"PeriodicalIF":4.3,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146004414","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":"IAP Antagonists Selectively Eliminate Therapy-Induced Senescent Cancer Cells via TNFα-Independent Apoptosis","authors":"Hiroaki Ochiiwa,&nbsp;Takeshi Wakasa,&nbsp;Yuki Kataoka,&nbsp;Koji Ando,&nbsp;Eiji Oki,&nbsp;Yoshihiko Maehara,&nbsp;Makoto Iimori,&nbsp;Hiroyuki Kitao","doi":"10.1111/cas.70329","DOIUrl":"10.1111/cas.70329","url":null,"abstract":"<p>Therapy-induced senescence (TIS) is a state in which cancer cells enter growth arrest following chemotherapy. TIS cancer cells influence the tumor microenvironment through their senescence-associated secretory phenotype and independently acquire stem-like properties, both of which contribute to increased aggressiveness and tumor relapse. Here, we show that AZD5582 and AT406, potent antagonists of cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1 and cIAP2) and X-linked inhibitor of apoptosis protein (XIAP), selectively eliminated HCT116 and RKO cells that had undergone senescence following treatment with a chemotherapeutic agent such as trifluridine, camptothecin, or doxorubicin. This elimination occurred via apoptosis associated with caspase 8 activation. These TIS cancer cells produced and secreted tumor necrosis factor α (TNFα); however, the selective cytotoxicity of IAP antagonists toward TIS cells was unexpectedly largely TNFα-independent. Consistently, the same IAP antagonists sensitized cancer cells treated with nutlin-3a, which induces senescence without TNFα production. Depletion of both cIAP1 and XIAP recapitulated the selective cytotoxicity against both TIS and nutlin-3a-induced senescent cancer cells. At physiological concentrations, TNFα sensitized non-senescent, proliferating cancer cells, but not TIS and nutlin-3a-induced senescent cancer cells, to apoptosis in the presence of IAP antagonists. Collectively, these findings suggest that IAP antagonists could serve as effective concomitant agents to TIS-inducing chemotherapy that promotes TNFα secretion within tumors, functioning not only as TNFα-independent senolytics but also as potentiators of TNFα-mediated apoptosis in adjacent non-senescent, proliferating cancer cells.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 4","pages":"1043-1056"},"PeriodicalIF":4.3,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146054683","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":"Cancer-Specific Antihuman Podoplanin Antibody chLpMab-2f Exerts Antitumor Effects Against Pleural Mesothelioma","authors":"Aito Yoshida,&nbsp;Shinji Abe,&nbsp;Toshihiro Izumi,&nbsp;Satoshi Itakura,&nbsp;Keichiro Yamada,&nbsp;Takuya Wada,&nbsp;Takaaki Yamamoto,&nbsp;Chiemi Sato,&nbsp;Atsushi Mitsuhashi,&nbsp;Hirokazu Ogino,&nbsp;Seidai Sato,&nbsp;Tsutomu Shinohara,&nbsp;Masaki Hanibuchi,&nbsp;Mika K. Kaneko,&nbsp;Yukinari Kato,&nbsp;Yasuhiko Nishioka","doi":"10.1111/cas.70325","DOIUrl":"10.1111/cas.70325","url":null,"abstract":"<p>Pleural mesothelioma (PM) is a malignancy with a poor prognosis owing to its resistance to chemotherapy. To develop a novel treatment for PM, podoplanin (PDPN), a transmembrane glycoprotein, has attracted significant attention because it is highly expressed in PM and is used for its diagnosis. We previously reported that NZ-12, a human chimeric antihuman PDPN antibody, exhibits antitumor effects against human PM cells through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Additionally, we developed a cancer-specific monoclonal antibody (CasMab) production technology and produced a mouse-human chimeric cancer-specific antihuman PDPN antibody, chLpMab-2, along with an afucosylated version, chLpMab-2f, to enhance ADCC activity. This study aimed to evaluate whether chLpMab-2f exhibits specific antitumor effects against PM in a preclinical model. We demonstrated that chLpMab-2f recognized the surface PDPN of human PM cell lines and human PM patient tissue but did not react with human normal tissues such as lung and kidney tissues. Furthermore, these antibodies exhibited ADCC and CDC activity against PDPN-positive PM cells while showing reduced toxicity toward non-malignant kidney-derived PDPN-positive cells, such as HEK-293FT. Additionally, chLpMab-2f demonstrated stronger ADCC activity through more efficient NK cell activation in comparison to chLpMab-2. Moreover, chLpMab-2f suppressed tumor progression in subcutaneously and intrathoracically transplanted human PM cells in mice. These findings suggest that PDPN-targeting immunotherapy with chLpMab-2f generated by CasMab technology could provide an effective treatment for PM with decreased toxicity toward normal tissues.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 4","pages":"917-928"},"PeriodicalIF":4.3,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146012923","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":"Targeting Wnt3a and Loxl2 Synergistically Induces Ferroptosis in Liver Cancer Stem Cells and Suppresses Tumorigenesis","authors":"Guanghui Ren,&nbsp;Qingwei Cong,&nbsp;Jing Wang,&nbsp;Wenyue Gao,&nbsp;Yunpeng Guan,&nbsp;Lianxin Zhu,&nbsp;Ying Zhu","doi":"10.1111/cas.70309","DOIUrl":"10.1111/cas.70309","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) has a poor prognosis and high mortality. Ferroptosis, an iron-dependent regulated cell death process, is implicated in cancer development and treatment. Wnt signaling and lysyl oxidase (Lox) family members are associated with ferroptosis. This study investigates how Wnt3a and/or Loxl2 knockdown affects liver cancer stem cells (LCSCs) and orthotopic tumor growth in mice, and explores the role of ferroptosis-related genes. Bioinformatics identified ferroptosis- and HCC-associated differentially expressed genes (DEGs) correlated with Wnt3a/Loxl2. LCSCs sorted from Hep3B were transduced with lentivirus for gene knockdown. Ferroptosis markers and DEG expression were analyzed. Wnt3a/Loxl2 knockout mice were generated using CRISPR-Cas9, and orthotopic tumor models were established. Tumor inhibition rates, ferroptosis-related indicators, and DEG expression were assessed. 199 ferroptosis-related DEGs were identified in HCC; ZEB1 was selected as a key gene via PPI analysis. Wnt3a/Loxl2 knockdown increased Fe²⁺ and MDA, and decreased GSH, most evidently in double-knockdown cells. In vivo, single- and double-knockout groups showed suppressed tumor growth, with inhibition rates of 51%, 71%, and 93%, respectively. Tumor tissues exhibited similar ferroptosis marker changes. ZEB1 was upregulated in both cellular and animal knockout models. Wnt3a/Loxl2 knockdown promotes ferroptosis in LCSCs and inhibits orthotopic tumor growth, with the strongest effect following dual-gene knockout. ZEB1 may be an important regulatory factor in this process.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 4","pages":"972-982"},"PeriodicalIF":4.3,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100579","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":"FB23-2 and Cisplatin Synergize to Inhibit Head and Neck Squamous Cell Carcinoma by Targeting the XPF/ERCC1 Complex","authors":"Yaoqi Jiang,&nbsp;Hongshi Cai,&nbsp;Yue Zhu,&nbsp;Jianfeng Liang,&nbsp;Hongyu Li,&nbsp;Fan Song,&nbsp;Ziyi Wang,&nbsp;Jinsong Hou","doi":"10.1111/cas.70322","DOIUrl":"10.1111/cas.70322","url":null,"abstract":"<p>Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy with a poor prognosis, often necessitating multimodal treatment approaches. While cisplatin (CDDP) remains the first-line chemotherapeutic agent, treatment failure frequently occurs due to drug resistance. To address this challenge, the FTO inhibitor FB23-2 has emerged as a promising candidate to enhance therapeutic efficacy. Consequently, this study aims to evaluate the combined efficacy of CDDP and FB23-2 in HNSCC and investigate their synergistic mechanisms. Using CCK-8 assays, colony formation assays, and flow cytometry for proliferation and cell cycle analysis, we observed that the CDDP-FB23-2 combination synergistically suppressed HNSCC proliferation. This treatment induced S/G2 phase cell cycle arrest and subsequent mitotic catastrophe. We further validated these findings in vivo using 4NQO-induced HNSCC mouse models. Additionally, drug safety was assessed via H&amp;E staining of visceral organs, which revealed that a semi-combined regimen reduced treatment-related side effects. Mechanistic investigations involving immunofluorescence (IF), quantitative real-time PCR (qRT-PCR), co-immunoprecipitation (Co-IP), and western blot analyses demonstrated that FB23-2 potentiated CDDP-induced DNA damage while inhibiting DNA repair mechanisms, thereby promoting apoptotic cell death. Specifically, FB23-2 blocked the assembly and nuclear translocation of XPF/ERCC1 complexes in CDDP-treated cells, directly increasing cellular sensitivity to CDDP. Collectively, our findings demonstrate that FB23-2 enhances CDDP sensitivity in HNSCC by targeting the XPF/ERCC1 complex, providing a theoretical basis and experimental support for their clinical application in HNSCC treatment.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 4","pages":"1010-1025"},"PeriodicalIF":4.3,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019922","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":"Impact of Sequential Ramucirumab Plus Docetaxel After PD-1 Inhibitors on Anti-PD-1 Antibody-Bound T-Cell Dynamics and Clinical Outcomes","authors":"Kinnosuke Matsumoto,&nbsp;Yujiro Naito,&nbsp;Takayuki Shiroyama,&nbsp;Motohiro Tamiya,&nbsp;Kazumi Nishino,&nbsp;Akihiro Tamiya,&nbsp;Kyoichi Okishio,&nbsp;Yuhei Kinehara,&nbsp;Tomoki Kuge,&nbsp;Masahide Mori,&nbsp;Shingo Satoh,&nbsp;Hidekazu Suzuki,&nbsp;Satoshi Tetsumoto,&nbsp;Toshie Niki,&nbsp;Yasuhiko Suga,&nbsp;Akio Osa,&nbsp;Toshiyuki Minami,&nbsp;Shohei Koyama,&nbsp;Yoshito Takeda,&nbsp;Nobuyuki Takakura,&nbsp;Atsushi Kumanogoh","doi":"10.1111/cas.70336","DOIUrl":"10.1111/cas.70336","url":null,"abstract":"<p>Ramucirumab plus docetaxel (RAM+DOC) demonstrates clinical activity after programmed cell death-1 (PD-1) inhibitors in advanced non-small cell lung cancer (NSCLC); however, the underlying mechanisms remain unclear. We aimed to evaluate clinical efficacy and explore immunologic dynamics and benefit-associated biomarkers. Patients treated with RAM+DOC after PD-1 inhibitors were enrolled in a multicenter prospective cohort. Anti-PD-1 antibody bound (IgG4⁺) T-cell subsets were measured at baseline (T0) and after 2–3 cycles (T1), reflecting residual anti-PD-1 antibody binding on circulating T cells. T1/T0 ratios of immune subsets were calculated to assess dynamics. Landmark analyses at T1 evaluated associations with progression-free survival (PFS) and overall survival (OS). Prognostic biomarkers were assessed at baseline. Among 27 evaluable patients, the objective response rate was 37.0%, median PFS 5.1 months, and OS 10.4 months. RAM + DOC responders had higher IgG4⁺CD8⁺ T-cell and lower IgG4⁺ Treg T1/T0 ratios (both <i>p</i> &lt; 0.001). Higher IgG4⁺CD8⁺ ratios were associated with longer landmark PFS (<i>p</i> = 0.002) and OS (<i>p</i> = 0.016) and were inversely correlated with IgG4⁺ Treg ratios (<i>p</i> = 0.008). Among the baseline factors, high IgG4⁺CD8⁺ Temra conferred survival benefits (OS, not reached vs. 8.2 months; <i>p</i> = 0.006), and low vascular endothelial growth factor (VEGF)-C levels were associated with longer OS (not reached vs. 8.5 months, <i>p</i> = 0.044). Both variables remained independent prognostic factors of PFS and OS in multivariable analysis. Our findings suggest that sequential strategy administering RAM+DOC during persistent binding of anti–PD-1 antibody to T cells may be beneficial. IgG4⁺CD8⁺ Temra and VEGF-C levels at RAM+DOC initiation may serve as biomarkers of survival benefit.</p><p><b>Trial Registration:</b> UMIN-Clinical Trials Registry (UMIN000050478)</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 4","pages":"929-942"},"PeriodicalIF":4.3,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146094448","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":"Roles of TIF1β in Leukemic Stem Cell Through SETDB1-Dependent and Independent Mechanisms","authors":"Mariko Morii,&nbsp;Sho Kubota,&nbsp;Goro Sashida","doi":"10.1111/cas.70334","DOIUrl":"10.1111/cas.70334","url":null,"abstract":"<p>TIF1β/TRIM28/KAP1 has been recognized as a scaffold protein that partners with KRAB-ZFPs and heterochromatin complexes to enforce gene silencing. In embryonic and pluripotent stem cells, it maintains self-renewal by silencing endogenous retroelements through the establishment of heterochromatin. While these canonical functions have been extensively examined in embryonic stem (ES) cells, accumulating evidence also highlights its diverse contributions to cancer biology. We herein focused on the oncogenic role of TIF1β in leukemic progression, contrasting this with its physiological roles in hematopoietic stem cell maintenance, differentiation, and immune regulation, thereby providing a comparative perspective on H3K9 methyltransferase SETDB1-dependent and -independent mechanisms. TIF1β-mediated epigenetic plasticity was recently shown to establish a leukemic chromatin environment for promoting oncogenic transcriptional programs while repressing lineage-differentiation regulators, which drives leukemic progression in a context-dependent manner. This review summarizes the dual role of TIF1β as a chromatin modulator, functioning both as a canonical transcriptional co-repressor and as a context-dependent co-activator, and also discusses how these modalities cooperate to sustain leukemic stem cell programs.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 4","pages":"896-903"},"PeriodicalIF":4.3,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146067987","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":"Targeting Genome Maintenance Defects of Cancers Using Chain-Terminating Nucleoside Analogs","authors":"Ryotaro Kawasumi,&nbsp;Rubaiat E. Tabassum,&nbsp;Kouji Hirota","doi":"10.1111/cas.70285","DOIUrl":"10.1111/cas.70285","url":null,"abstract":"<p>Conventional cancer therapies, including radiation therapy and chemotherapy, rely on inflicting DNA damage, yet they inevitably affect normal cells, leading to severe adverse effects. The advent of precision chemotherapy exploiting tumor-specific DNA repair defects has validated the effectiveness of this approach. The first successful example is PARP inhibitors, which selectively kill homologous recombination (HR) defective cancers, such as familial breast cancer possessing HR deficiency due to <i>BRCA</i> gene mutations. However, the broader landscape of DNA maintenance—including DNA replication, repair, and checkpoint pathways—harbors numerous mutations in tumors that remain untargeted. Here, we propose repurposing chain-terminating nucleoside analogs (CTNAs) to target such cancers' vulnerabilities. CTNAs, long utilized as anti-cancers and anti-viral drugs, inhibit replication and thereby suppress growth, but their activity has never been systematically aligned with specific cancer mutations associated with DNA maintenance defects. Based on our recent studies, we demonstrate that CTNAs elicit synthetic lethality in cells deficient for distinct DNA maintenance systems, amplifying replication stress, leading to cell death. We highlight the spectrum of CTNA-induced lesions and repair pathways required for cellular tolerance. This framework presents a versatile “repair-defect-guided” chemotherapy that expands the clinical utility of CTNAs and improves therapeutic effect by reducing side effects.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 3","pages":"587-596"},"PeriodicalIF":4.3,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726714","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":"Precision Oncology for Pediatric Solid Tumors Using In-Hospital Pediatric/AYA Malignancy-Specific Panel Sequencing","authors":"Masato Kojima,&nbsp;Sho Kurihara,&nbsp;Isamu Saeki,&nbsp;Ryo Touge,&nbsp;Keigo Nakashima,&nbsp;Shuhei Karakawa,&nbsp;Fumiyuki Yamasaki,&nbsp;Satoshi Okada,&nbsp;Eiso Hiyama","doi":"10.1111/cas.70312","DOIUrl":"10.1111/cas.70312","url":null,"abstract":"<p>Precision oncology, based on the genomic profile of tumors, is increasing in cancer treatment. It is important in pediatric and adolescent and young adult (AYA) malignancies, a group of rare cancers that are difficult to diagnose and progress quickly. We evaluated the usefulness of in-hospital molecular profiling using a specific sequencing panel for pediatric and AYA malignancies in clarifying the diagnosis, predicting the prognosis, and identifying therapeutic targets. We evaluated the Oncomine Childhood Cancer Research Assay (203 genes, 1700 fusions) and analyzed 153 samples at diagnosis and 34 samples at relapse or refractory from 165 pediatric and AYA patients with various solid malignancies, including neuroblastoma, hepatoblastoma, brain tumor, and sarcoma. We simulated in-hospital molecular profiling. In total, 320 reportable variants were identified in 153 samples (81.8%). Variants with clinical significance were identified in 62 samples (33.1%), including diagnostic variants in 26 (13.9%), prognostic variants in 17 (9%), targetable variants in 41 (21.9%), and variants with drug resistance in 18 (9.6%). Additionally, 62.0% and 94.1% of identified diagnostic and prognostic variants, respectively, had high levels of evidence. In five patients with cancer predisposition syndromes, all pathogenic germline mutations were validated. The turnaround time (TAT) from sample collection to reporting of the molecular profile was within seven working days. In-hospital molecular profiling using a sequencing panel specified tailored for pediatric and AYA malignancies has a high rate of identifying reportable variants and enables accurate diagnosis, malignancy grading, and treatment selection, as well as cancer predisposition syndromes with a short TAT.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 3","pages":"797-806"},"PeriodicalIF":4.3,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850663","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}