Cancer Communications最新文献

{"title":"4-1BB transcriptomic expression patterns across malignancies: Implications for clinical trials of 4-1BB agonists","authors":"Yuji Uehara, Shumei Kato, Daisuke Nishizaki, Hirotaka Miyashita, Suzanna Lee, Mary K. Nesline, Sarabjot Pabla, Jeffrey M. Conroy, Paul DePietro, Heidi Ko, Jason K. Sicklick, Razelle Kurzrock","doi":"10.1002/cac2.12592","DOIUrl":"10.1002/cac2.12592","url":null,"abstract":"<p>4-1BB, a member of the tumor necrosis factor receptor superfamily, is an important co-stimulatory molecule regulating the activity of immune cells across a range of physiological and pathological processes, which culminates in a potent immune response (Figure 1A and B) [<span>1, 2</span>]. Numerous clinical trials have been conducted utilizing 4–1BB agonists (Supplemental Table S1); however, previous and ongoing 4-1BB agonist trials are being conducted without biomarker selection, which potentially explains their modest efficacy. Interestingly, several studies suggest the potential value of utilizing transcriptomics in addition to genomics to identify the unique immunologic signature of individual tumors [<span>3-7</span>].</p><p>Herein, we explore the landscape of 4–1BB transcriptomic profiles in 514 patients, including 489 with advanced/metastatic cancers and clinical annotation, and we discuss the potential therapeutic implications of the observed patterns and heterogeneity. The study methods are provided in the Supplementary File.</p><p>There were 514 tumors reflecting 31 different cancer types evaluated (Supplemental Table S2). Their median age was 61 (range, 24-93) years; 310 (60.3%) were women. The most frequent tumor types assessed were colorectal cancer (<i>n</i> = 140 samples). Of the 514 patients, 489 had confirmed metastatic or locally advanced disease, but the dates of metastatic disease for 25 patients were not documented. Overall, 489 patients with advanced/metastatic disease had fully evaluable clinical correlative data (Figure 1C). In total, 217 patients received ICIs; 199 received anti-programmed cell death 1 (PD-1)/ programmed death-ligand 1 (PD-L1) monotherapy, 2 received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monotherapy, and 16 received a combination of anti-PD-1/PD-L1 and anti-CTLA-4. The remaining 272 patients never received immunotherapy.</p><p>Figure 1D demonstrates the variations in 4-1BB RNA expression across different cancer types: 4-1BB ribonucleic acid (RNA) expression was classified as “high” (75-100th percentile), “moderate” (25-74th percentile), and “low” (0-24th percentile). Among all cancers (<i>n</i> = 514), 77 (15.0%) had high, 268 (52.1%) had moderate, and 169 (32.9%) had low 4-1BB expression. Small intestine and ovarian cancers most frequently had high 4-1BB RNA expression (25.0% and 20.9% of tumors, respectively).</p><p>To identify the patient population who might theoretically benefit the most from 4-1BB agonism, the proportion of patients having high 4-1BB expression along with low/moderate 4-1BB ligand (4-1BBL) expression was assessed in malignancies that had more than 20 representative samples (from a biologic point of view, high receptor with low/moderate ligand might be most amenable to treatment with 4-1BB agonists in the clinic). Malignancies with the highest proportion of patients having both high 4-1BB expression and low/moderate 4-1BBL expression were ovarian and pancreatic","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 10","pages":"1168-1172"},"PeriodicalIF":20.1,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12592","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888502","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":"Beyond the Gut: The intratumoral microbiome's influence on tumorigenesis and treatment response","authors":"Hao Zhang,&nbsp;Li Fu,&nbsp;Xinwen Leiliang,&nbsp;Chunrun Qu,&nbsp;Wantao Wu,&nbsp;Rong Wen,&nbsp;Ning Huang,&nbsp;Qiuguang He,&nbsp;Quan Cheng,&nbsp;Guodong Liu,&nbsp;Yuan Cheng","doi":"10.1002/cac2.12597","DOIUrl":"10.1002/cac2.12597","url":null,"abstract":"<p>The intratumoral microbiome (TM) refers to the microorganisms in the tumor tissues, including bacteria, fungi, viruses, and so on, and is distinct from the gut microbiome and circulating microbiota. TM is strongly associated with tumorigenesis, progression, metastasis, and response to therapy. This paper highlights the current status of TM. Tract sources, adjacent normal tissue, circulatory system, and concomitant tumor co-metastasis are the main origin of TM. The advanced techniques in TM analysis are comprehensively summarized. Besides, TM is involved in tumor progression through several mechanisms, including DNA damage, activation of oncogenic signaling pathways (phosphoinositide 3-kinase [PI3K], signal transducer and activator of transcription [STAT], WNT/β-catenin, and extracellular regulated protein kinases [ERK]), influence of cytokines and induce inflammatory responses, and interaction with the tumor microenvironment (anti-tumor immunity, pro-tumor immunity, and microbial-derived metabolites). Moreover, promising directions of TM in tumor therapy include immunotherapy, chemotherapy, radiotherapy, the application of probiotics/prebiotics/synbiotics, fecal microbiome transplantation, engineered microbiota, phage therapy, and oncolytic virus therapy. The inherent challenges of clinical application are also summarized. This review provides a comprehensive landscape for analyzing TM, especially the TM-related mechanisms and TM-based treatment in cancer.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 10","pages":"1130-1167"},"PeriodicalIF":20.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12597","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859128","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":"Advances and clinical applications of immune checkpoint inhibitors in hematological malignancies","authors":"Wenyue Sun,&nbsp;Shunfeng Hu,&nbsp;Xin Wang","doi":"10.1002/cac2.12587","DOIUrl":"10.1002/cac2.12587","url":null,"abstract":"<p>Immune checkpoints are differentially expressed on various immune cells to regulate immune responses in tumor microenvironment. Tumor cells can activate the immune checkpoint pathway to establish an immunosuppressive tumor microenvironment and inhibit the anti-tumor immune response, which may lead to tumor progression by evading immune surveillance. Interrupting co-inhibitory signaling pathways with immune checkpoint inhibitors (ICIs) could reinvigorate the anti-tumor immune response and promote immune-mediated eradication of tumor cells. As a milestone in tumor treatment, ICIs have been firstly used in solid tumors and subsequently expanded to hematological malignancies, which are in their infancy. Currently, immune checkpoints have been investigated as promising biomarkers and therapeutic targets in hematological malignancies, and novel immune checkpoints, such as signal regulatory protein α (SIRPα) and tumor necrosis factor-alpha-inducible protein 8-like 2 (TIPE2), are constantly being discovered. Numerous ICIs have received clinical approval for clinical application in the treatment of hematological malignancies, especially when used in combination with other strategies, including oncolytic viruses (OVs), neoantigen vaccines, bispecific antibodies (bsAb), bio-nanomaterials, tumor vaccines, and cytokine-induced killer (CIK) cells. Moreover, the proportion of individuals with hematological malignancies benefiting from ICIs remains lower than expected due to multiple mechanisms of drug resistance and immune-related adverse events (irAEs). Close monitoring and appropriate intervention are needed to mitigate irAEs while using ICIs. This review provided a comprehensive overview of immune checkpoints on different immune cells, the latest advances of ICIs and highlighted the clinical applications of immune checkpoints in hematological malignancies, including biomarkers, targets, combination of ICIs with other therapies, mechanisms of resistance to ICIs, and irAEs, which can provide novel insight into the future exploration of ICIs in tumor treatment.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 9","pages":"1071-1097"},"PeriodicalIF":20.1,"publicationDate":"2024-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12587","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787311","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":"Abrogation of nuclear entry of TERT by fructose 1,6-bisphosphatase 1-mediated dephosphorylation","authors":"Pengbo Yao,&nbsp;Gaoxiang Zhao,&nbsp;Min Li,&nbsp;Wensheng Qiu,&nbsp;Zhimin Lu","doi":"10.1002/cac2.12599","DOIUrl":"10.1002/cac2.12599","url":null,"abstract":"&lt;p&gt;Telomeres maintain chromosome integrity. Loss of telomere function, which is attributed to progressively shortened telomeres in each round of DNA replication, induces end-to-end fusion of chromosomes, anaphase bridges with subsequent chromosome breakage, and eventually leads to senescence and apoptosis in normal cells [&lt;span&gt;1&lt;/span&gt;]. In cancer cells, highly activated telomerase synthesizes telomere repeats to promote telomere elongation. For assembling catalytically active telomerase, cytoplasmic telomerase reverse transcriptase (TERT), which is the catalytic protein subunit of telomerase, needs to translocate into the nucleus. This translocation requires AKT-mediated TERT S227 phosphorylation and subsequent binding of the nuclear localization signal (NLS) of TERT to importin α [&lt;span&gt;2&lt;/span&gt;]. However, whether cancer cells and normal cells differentially regulate TERT phosphorylation and telomere functions remain largely unknown.&lt;/p&gt;&lt;p&gt;We recently demonstrated that fructose 1,6-bisphosphatase 1 (FBP1), the rate-limiting gluconeogenic enzyme that converts fructose 1,6-bisphosphate (F-1,6-BP) to fructose 6-phosphate (F-6-P), acts as a protein phosphatase and dephosphorylates TERT [&lt;span&gt;3&lt;/span&gt;]. Through analyses of FBP1 immunoprecipitants from hepatocellular carcinoma (HCC) Huh7 cells by mass spectrometry, TERT was identified as an FBP1-associated protein, and this interaction was primarily in the cytosol. An in vitro glutathione S-transferase (GST) pulldown assay showed that FBP1 directly bound to TERT, and truncation and mutagenesis analyses identified that asparagine (N)273 of FBP1 is a key residue involving in binding to TERT. Importantly, a protein dephosphorylation assay showed that wild-type (WT) FBP1, but not FBP1 N273A mutant, dephosphorylated AKT1-phosphorylated TERT at S227. Notably, FBP1 G260R, a metabolically inactive mutant defected in its binding to F-1,6-BP, was still able to dephosphorylate TERT, indicating that FBP1 dephosphorylates TERT independent of its gluconeogenic activity.&lt;/p&gt;&lt;p&gt;The catalytic domain of conventional protein phosphatases contains a conserved and reduced cysteine (C), which is critical for the dephosphorylation of protein substrates. Molecular docking analyses showed that the phosphorylated S227 residue of TERT was in close proximity to C129 of FBP1 [&lt;span&gt;3&lt;/span&gt;]. In addition, during the process of the dephosphorylation, FBP1 formed a covalent phospho-C129 intermediate. FBP1 C129S mutant, which had comparable metabolic activity to its WT counterpart, lost its ability to dephosphorylate TERT pS227 both in vitro and in vivo. Structural analyses revealed that a binding pocket was formed by FBP1 C129, R244 and D128, which interact with the phosphate group of pS227 of TERT. Notably, mutations of FBP1 R244 or D128 also decreased TERT pS227 dephosphorylation by FBP1.&lt;/p&gt;&lt;p&gt;As expected, FBP1 depletion enhanced the nuclear translocation of TERT and telomerase activity, leading to increased telomere lengths ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 10","pages":"1102-1105"},"PeriodicalIF":20.1,"publicationDate":"2024-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12599","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787310","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":"Galectin 3-binding protein (LGALS3BP) depletion attenuates hepatic fibrosis by reducing transforming growth factor-β1 (TGF-β1) availability and inhibits hepatocarcinogenesis","authors":"Dae-Hwan Kim,&nbsp;Minjeong Sung,&nbsp;Myong-Suk Park,&nbsp;Eun-Gene Sun,&nbsp;Sumin Yoon,&nbsp;Kyung Hyun Yoo,&nbsp;Kamalakannan Radhakrishnan,&nbsp;Sung Yun Jung,&nbsp;Woo-Kyun Bae,&nbsp;Sang-Hee Cho,&nbsp;Ik-Joo Chung","doi":"10.1002/cac2.12600","DOIUrl":"10.1002/cac2.12600","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Increased Galectin 3-binding protein (LGALS3BP) serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma (HCC). Considering the crucial role of transforming growth factor-β1 (TGF-β1) in the emergence of these diseases, the present study tested the hypothesis that LGALS3BP regulates the TGF-β1 signaling pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The expression levels of <i>LGALS3BP</i> and <i>TGFB1</i> were analyzed in patients with metabolic dysfunction-associated steatohepatitis (MASH) and HCC. Multiple omics techniques, such as RNA-sequencing, transposase-accessible chromatin-sequencing assay, and liquid chromatography-tandem mass spectrometry proteomics, were used to identify the regulatory mechanisms for the LGALS3BP-TGF-β1 axis. The effects of altered TGF-β1 signaling by LGALS3BP were investigated in conditional <i>LGALS3BP</i>-knockin and <i>LGALS3BP</i>-knockout mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In patients with MASH and HCC, the levels of <i>LGALS3BP</i> and <i>TGFB1</i> exhibited positive correlations. Stimulation of LGALS3BP by the inflammatory cytokine interferon α in HCC cells or ectopic overexpression of LGALS3BP in hepatocytes promoted the expression levels of TGFB1. Aggravated fibrosis was observed in the livers of hepatocyte-specific <i>LGALS3BP</i>-knockin mice, with increased TGFB1 levels. LGALS3BP directly bound to and assembled integrin αV, an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin cytoskeleton. The released TGF-β1 activated JunB transcription factor, which in turn promoted the TGF-β1 positive feedback loop. <i>LGALS3BP</i> deletion in the hepatocytes downregulated TGF-β1 signaling and CCl₄ induced fibrosis. Moreover, <i>LGALS3BP</i> depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>LGALS3BP plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway, making it a promising therapeutic target in TGF-β1-related diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 10","pages":"1106-1129"},"PeriodicalIF":20.1,"publicationDate":"2024-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12600","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787312","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":"Dysfunction of dendritic cells in tumor microenvironment and immunotherapy","authors":"Jie Chen,&nbsp;Yuhang Duan,&nbsp;Junye Che,&nbsp;Jianwei Zhu","doi":"10.1002/cac2.12596","DOIUrl":"10.1002/cac2.12596","url":null,"abstract":"<p>Dendritic cells (DCs) comprise diverse cell populations that play critical roles in antigen presentation and triggering immune responses in the body. However, several factors impair the immune function of DCs and may promote immune evasion in cancer. Understanding the mechanism of DC dysfunction and the diverse functions of heterogeneous DCs in the tumor microenvironment (TME) is critical for designing effective strategies for cancer immunotherapy. Clinical applications targeting DCs summarized in this report aim to improve immune infiltration and enhance the biological function of DCs to modulate the TME to prevent cancer cells from evading the immune system. Herein, factors in the TME that induce DC dysfunction, such as cytokines, hypoxic environment, tumor exosomes and metabolites, and co-inhibitory molecules, have been described. Furthermore, several key signaling pathways involved in DC dysfunction and signal-relevant drugs evaluated in clinical trials were identified. Finally, this review provides an overview of current clinical immunotherapies targeting DCs, especially therapies with proven clinical outcomes, and explores future developments in DC immunotherapies.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 9","pages":"1047-1070"},"PeriodicalIF":20.1,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12596","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757320","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":"Efficacy, safety and biomarkers of SG001 for patients with previously treated recurrent or metastatic cervical cancer: an open-label, multicenter, phase Ib trial","authors":"Jing Zuo,&nbsp;Wei Duan,&nbsp;Mingxuan Zhao,&nbsp;Zhendong Chen,&nbsp;Jie Lin,&nbsp;Huaqiu Shi,&nbsp;Ou Jiang,&nbsp;Youzhong Zhang,&nbsp;Meiyu Fang,&nbsp;Li Wang,&nbsp;Wei Wang,&nbsp;Yong Huang,&nbsp;Junyan Yu,&nbsp;Xiaoxue Zhang,&nbsp;Weiqing Pu,&nbsp;Deshun Hao,&nbsp;Fenglin She,&nbsp;Xiugao Yang,&nbsp;Ying Chen,&nbsp;Qizhi Tang,&nbsp;Xiao Zhang,&nbsp;Miao Niu,&nbsp;Yan'e Song,&nbsp;Lingying Wu","doi":"10.1002/cac2.12578","DOIUrl":"10.1002/cac2.12578","url":null,"abstract":"&lt;p&gt;Cervical cancer (CC) is one of the most common gynecological cancers, ranking fourth in incidence and mortality rates among women worldwide and second in China [&lt;span&gt;1&lt;/span&gt;]. Approximately 15%-61% of patients with CC develop recurrent or metastatic (r/m) disease in the first two years after initial therapy completion, with a 5-year survival rate of 17% [&lt;span&gt;2&lt;/span&gt;]. Platinum-based chemotherapy is the first-line treatment for r/mCC.&lt;/p&gt;&lt;p&gt;The immune checkpoint inhibitors targeting the programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway have provided promising therapeutic choices [&lt;span&gt;3, 4&lt;/span&gt;]. Based on the results from the KEYNOTE-158 [&lt;span&gt;5&lt;/span&gt;] and KEYNOTE-826 trials [&lt;span&gt;3&lt;/span&gt;], pembrolizumab has been approved by the U.S. Food and Drug Administration (FDA) as first-line (in combination with chemotherapy, with or without bevacizumab) and second-line or subsequent treatments for patients with PD-L1-positive r/mCC. However, the objective response rate (ORR) of PD-L1 inhibitor monotherapies rarely exceeds 30% in patients with PD-L1-positive r/mCC [&lt;span&gt;4, 6, 7&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;SG001 is a fully humanized and high-affinity immunoglobulin G4 monoclonal antibody that targets PD-1 to block its interaction with the ligands PD-L1 and PD-L2. Here, we present the results from an expansion cohort (previously treated r/mCC) of an open-label, multicenter, phase Ib trial of SG001 monotherapy in patients with multiple advanced cancers (NCT03852823). Patients with histologically confirmed r/mCC who had progressed or were intolerant after one or more lines of chemotherapy and had at least one measurable lesion per the Response Evaluation Criteria in Advanced Solid Tumors (RECIST, version 1.1) were enrolled. SG001 (240 mg) was administered intravenously every 2 weeks until progressive disease, intolerable toxicity, or withdrawal. The methods for this study are described in detail in the Supplementary Material file.&lt;/p&gt;&lt;p&gt;A total of 91 patients were enrolled (Supplementary Figure S1). Ninety (98.9%) patients had received prior platinum-based therapy and 83 (91.2%) patients had undergone previous radiotherapy. In addition, 73 (80.2%) patients had squamous cell carcinoma (SCC), and 78 (85.7%) patients had distant metastasis. Forty-three (47.3%) patients had PD-L1-positive tumors (combined positive score ≥ 1). The baseline characteristics are summarized in Supplementary Table S1.&lt;/p&gt;&lt;p&gt;The Independent Review Committee (IRC)-assessed ORR was 25.3% (95% CI, 16.7-35.5), 29 (31.9%) of patients had stable disease (SD), and the disease control rate (DCR) was 63.7% (95% CI, 53.0-73.6) (Figure 1A and Supplementary Table S2). The median time to response (TTR) was 1.4 months (95% CI, 1.4-2.7). The median duration of response (DoR) had not been reached, with a 12-month DoR rate of 62.4% (95% CI, 35.7-80.5) (Supplementary Table S2). Thirty-nine patients exhibited a reduction in the target lesion size from baseline (Figure 1B). Similar results of the ORR,","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 9","pages":"1042-1046"},"PeriodicalIF":20.1,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12578","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751183","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":"Targeting N4-acetylcytidine suppresses hepatocellular carcinoma progression by repressing eEF2-mediated HMGB2 mRNA translation","authors":"Hailing Liu,&nbsp;Lei Xu,&nbsp;Shiwei Yue,&nbsp;Hongfei Su,&nbsp;Xing Chen,&nbsp;Qiumeng Liu,&nbsp;Hui Li,&nbsp;Huifang Liang,&nbsp;Xiaoping Chen,&nbsp;Jiefeng He,&nbsp;Zeyang Ding,&nbsp;Bixiang Zhang","doi":"10.1002/cac2.12595","DOIUrl":"10.1002/cac2.12595","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;N4-acetylcytidine (ac4C) represents a novel messenger RNA (mRNA) modification, and its associated acetyltransferase N-acetyltransferase 10 (NAT10) plays a crucial role in the initiation and progression of tumors by regulating mRNA functionality. However, its role in hepatocellular carcinoma (HCC) development and prognosis is largely unknown. This study aimed to elucidate the role of NAT10-mediated ac4C in HCC progression and provide a promising therapeutic approach.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The ac4C levels were evaluated by dot blot and ultra-performance liquid chromatography-tandem mass spectrometry with harvested HCC tissues. The expression of NAT10 was investigated using quantitative real-time polymerase chain reaction, western blotting, and immunohistochemical staining across 91 cohorts of HCC patients. To explore the underlying mechanisms of NAT10-ac4C in HCC, we employed a comprehensive approach integrating acetylated RNA immunoprecipitation and sequencing, RNA sequencing and ribosome profiling analyses, along with RNA immunoprecipitation, RNA pull-down, mass spectrometry, and site-specific mutation analyses. The drug affinity responsive targets stability, cellular thermal shift assay, and surface plasmon resonance assays were performed to assess the specific binding of NAT10 and Panobinostat. Furthermore, the efficacy of targeting NAT10-ac4C for HCC treatment was elucidated through in vitro experiments using HCC cells and in vivo HCC mouse models.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our investigation revealed a significant increase in both the ac4C RNA level and NAT10 expression in HCC. Notably, elevated NAT10 expression was associated with poor outcomes in HCC patients. Functionally, silencing NAT10 suppressed HCC proliferation and metastasis in &lt;i&gt;vitro&lt;/i&gt; and in vivo. Mechanistically, NAT10 stimulates the ac4C modification within the coding sequence (CDS) of high mobility group protein B2 (HMGB2), which subsequently enhances HMGB2 translation by facilitating eukaryotic elongation factor 2 (eEF2) binding to the ac4C sites on HMGB2 mRNA's CDS. Additionally, high-throughput compound library screening revealed Panobinostat as a potent inhibitor of NAT10-mediated ac4C modification. This inhibition significantly attenuated HCC growth and metastasis in both in vitro experiments using HCC cells and in vivo HCC mouse models.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our study identified a novel oncogenic epi-transcriptome axis involving NAT10-ac4C/eEF2-HMGB2, which pla","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 9","pages":"1018-1041"},"PeriodicalIF":20.1,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12595","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731006","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":"Real-world data on ALK rearrangement test in Chinese advanced non-small cell lung cancer (RATICAL): a nationwide multicenter retrospective study","authors":"Lin Li,&nbsp;Wencai Li,&nbsp;Chunyan Wu,&nbsp;Yanfeng Xi,&nbsp;Lei Guo,&nbsp;Yuan Ji,&nbsp;Lili Jiang,&nbsp;Ji Li,&nbsp;Jingping Yun,&nbsp;Gang Chen,&nbsp;Yuan Li,&nbsp;Yueping Liu,&nbsp;Dianbin Mu,&nbsp;Yuchen Han,&nbsp;Leina Sun,&nbsp;Qingxin Xia,&nbsp;Xiaodong Teng,&nbsp;Nanying Che,&nbsp;Wei Wu,&nbsp;Xueshan Qiu,&nbsp;Chao Liu,&nbsp;Xiaochu Yan,&nbsp;Daiqiang Li,&nbsp;Zhihong Zhang,&nbsp;Zhe Wang,&nbsp;Yujun Li,&nbsp;Zheng Wang,&nbsp;Lingchuan Guo,&nbsp;Xiu Nie,&nbsp;Jingshu Geng,&nbsp;Jianhua Zhou,&nbsp;Jianming Ying","doi":"10.1002/cac2.12593","DOIUrl":"10.1002/cac2.12593","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Anaplastic lymphoma kinase (&lt;i&gt;ALK&lt;/i&gt;) test in advanced non-small cell lung cancer (NSCLC) can help physicians provide target therapies for patients harboring &lt;i&gt;ALK&lt;/i&gt; gene rearrangement. This study aimed to investigate the real-world test patterns and positive rates of &lt;i&gt;ALK&lt;/i&gt; gene rearrangements in advanced NSCLC.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In this real-world study (ChiCTR2000030266), patients with advanced NSCLC who underwent an &lt;i&gt;ALK&lt;/i&gt; rearrangement test in 30 medical centers in China between October 1, 2018 and December 31, 2019 were retrospectively analyzed. Interpretation training was conducted before the study was initiated. Quality controls were performed at participating centers using immunohistochemistry (IHC)-VENTANA-D5F3. The positive &lt;i&gt;ALK&lt;/i&gt; gene rearrangement rate and consistency rate were calculated. The associated clinicopathological characteristics of &lt;i&gt;ALK&lt;/i&gt; gene rearrangement were investigated as well.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The overall &lt;i&gt;ALK&lt;/i&gt; gene rearrangement rate was 6.7% in 23,689 patients with advanced NSCLC and 8.2% in 17,436 patients with advanced lung adenocarcinoma. The quality control analysis of IHC-VENTANA-D5F3 revealed an intra-hospital consistency rate of 98.2% (879/895) and an inter-hospital consistency rate of 99.2% (646/651). IHC-VENTANA-D5F3 was used in 53.6%, real-time polymerase chain reaction (RT-PCR) in 25.4%, next-generation sequencing (NGS) in 18.3%, and fluorescence in-situ hybridization (FISH) in 15.9% in the adenocarcinoma subgroup. For specimens tested with multiple methods, the consistency rates confirmed by IHC-VENTANA-D5F3 were 98.0% (822/839) for FISH, 98.7% (1,222/1,238) for NGS, and 91.3% (146/160) for RT-PCR. The overall &lt;i&gt;ALK&lt;/i&gt; gene rearrangement rates were higher in females, patients of ≤ 35 years old, never smokers, tumor cellularity of &gt; 50, and metastatic specimens used for testing in the total NSCLC population and adenocarcinoma subgroup (all &lt;i&gt;P&lt;/i&gt; &lt; 0.05).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study highlights the real-world variability and challenges of &lt;i&gt;ALK&lt;/i&gt; test in advanced NSCLC, demonstrating a predominant use of IHC-VENTANA-D5F3 with high consistency and distinct clinicopathological features in &lt;i&gt;ALK&lt;/i&gt;-positive patients. These findings underscore the need for a consensus on optimal test practices and support the development of refined &lt;i&gt;ALK&lt;/i&gt; test strategies to enhance diagnostic accuracy and therapeutic decision-making in NSCLC.&lt;/p&gt;\u0000 ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 9","pages":"992-1004"},"PeriodicalIF":20.1,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12593","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626091","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":"Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS)","authors":"Shun Lu,&nbsp;Xiaorong Dong,&nbsp;Hong Jian,&nbsp;Jianhua Chen,&nbsp;Gongyan Chen,&nbsp;Yuping Sun,&nbsp;Yinghua Ji,&nbsp;Ziping Wang,&nbsp;Jianhua Shi,&nbsp;Junguo Lu,&nbsp;Shaoshui Chen,&nbsp;Dongqing Lv,&nbsp;Guojun Zhang,&nbsp;Chunling Liu,&nbsp;Juan Li,&nbsp;Xinmin Yu,&nbsp;Zhong Lin,&nbsp;Zhuang Yu,&nbsp;Zhehai Wang,&nbsp;Jiuwei Cui,&nbsp;Xingxiang Xu,&nbsp;Jian Fang,&nbsp;Jifeng Feng,&nbsp;Zhi Xu,&nbsp;Rui Ma,&nbsp;Jie Hu,&nbsp;Nong Yang,&nbsp;Xiangdong Zhou,&nbsp;Xiaohong Wu,&nbsp;Chengping Hu,&nbsp;Zhihong Zhang,&nbsp;You Lu,&nbsp;Yanping Hu,&nbsp;Liyan Jiang,&nbsp;Qiming wang,&nbsp;Renhua Guo,&nbsp;Jianying Zhou,&nbsp;Baolan Li,&nbsp;Chunhong Hu,&nbsp;Wancheng Tong,&nbsp;Helong Zhang,&nbsp;Lin Ma,&nbsp;Yuan Chen,&nbsp;Zhijun Jie,&nbsp;Yu Yao,&nbsp;Longzhen Zhang,&nbsp;Jie Weng,&nbsp;Weidong Li,&nbsp;Jianping Xiong,&nbsp;Xianwei Ye,&nbsp;Jianchun Duan,&nbsp;Haihua Yang,&nbsp;Meili Sun,&nbsp;Hongying Wei,&nbsp;Jiawei Wei,&nbsp;Zheyu Zhang,&nbsp;Qiong Wu","doi":"10.1002/cac2.12594","DOIUrl":"10.1002/cac2.12594","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (&lt;i&gt;EGFR&lt;/i&gt;)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; &lt;i&gt;P&lt;/i&gt; &lt; 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; &lt;i&gt;P&lt;/i&gt; &lt; 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with &lt;i&gt;EGFR&lt;/i&gt;-mutated advanced NSCLC with baseline CNS metastases.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Trial registration&lt;/h3&gt;\u0000 \u0000 ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 9","pages":"1005-1017"},"PeriodicalIF":20.1,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12594","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626090","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}