Pub Date : 2024-03-21DOI: 10.1038/s41571-024-00885-z
David Killock
{"title":"IL-13Rα2-targeted CAR T cells show promise in patients with recurrent high-grade gliomas","authors":"David Killock","doi":"10.1038/s41571-024-00885-z","DOIUrl":"10.1038/s41571-024-00885-z","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140185033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-20DOI: 10.1038/s41571-024-00884-0
Peter Sidaway
{"title":"A new standard of care for advanced-stage urothelial carcinoma","authors":"Peter Sidaway","doi":"10.1038/s41571-024-00884-0","DOIUrl":"10.1038/s41571-024-00884-0","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-20DOI: 10.1038/s41571-024-00882-2
Saman Maleki Vareki, Diwakar Davar
The composition of the gut microbiota has emerged as a tumour-extrinsic factor that modulates response to immune-checkpoint inhibitors (ICIs), although the lack of consistency in microbiota signatures across studies has limited their value as reliable biomarkers. Herein, we discuss a recent study in which longitudinal microbiome profiling identified several taxa that are persistently enriched in patients with melanoma and a favourable response to ICIs.
{"title":"Identification of dynamic microbiota signatures in patients with melanoma receiving ICIs: opportunities and challenges","authors":"Saman Maleki Vareki, Diwakar Davar","doi":"10.1038/s41571-024-00882-2","DOIUrl":"10.1038/s41571-024-00882-2","url":null,"abstract":"The composition of the gut microbiota has emerged as a tumour-extrinsic factor that modulates response to immune-checkpoint inhibitors (ICIs), although the lack of consistency in microbiota signatures across studies has limited their value as reliable biomarkers. Herein, we discuss a recent study in which longitudinal microbiome profiling identified several taxa that are persistently enriched in patients with melanoma and a favourable response to ICIs.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-19DOI: 10.1038/s41571-024-00874-2
Izuma Nakayama, Changsong Qi, Yang Chen, Yoshiaki Nakamura, Lin Shen, Kohei Shitara
Claudin 18.2, a tight-junction molecule predominantly found in the nonmalignant gastric epithelium, becomes accessible on the tumour cell surface during malignant transformation, thereby providing an appealing target for cancer therapy. Data from two phase III trials testing the anti-claudin 18.2 antibody zolbetuximab have established claudin 18.2-positive advanced-stage gastric cancers as an independent therapeutic subset that derives benefit from the addition of this agent to chemotherapy. This development has substantially increased the percentage of patients eligible for targeted therapy. Furthermore, newer treatments, such as high-affinity monoclonal antibodies, bispecific antibodies, chimeric antigen receptor T cells and antibody–drug conjugates capable of bystander killing effects, have shown considerable promise in patients with claudin 18.2-expressing gastric cancers. This new development has resulted from drug developers moving beyond traditional targets, such as driver gene alterations or growth factors. In this Review, we highlight the biological rationale and explore the clinical activity of therapies that target claudin 18.2 in patients with advanced-stage gastric cancer and explore the potential for expansion of claudin 18.2-targeted therapies to patients with other claudin 18.2-positive solid tumours. The development and successful phase III testing of the anti-claudin 18.2 antibody zolbetuximab has provided a novel targeted therapy for the 30–40% of patients with strongly claudin 18.2-positive gastric cancers. Furthermore, the development of an effective targeted therapy for a target that does not have a driver role in cancer development provides a novel drug development paradigm. In this Review, the authors describe the development of claudin 18.2-targeted therapies, including zolbetuximab, as well as novel therapies, including chimeric antigen receptor (CAR) T cells, antibody–drug conjugates and bispecific antibodies, all of which have the potential to expand the number of patients who can derive benefit from claudin 18.2-targeted therapies in the near future.
克劳丁 18.2 是一种紧密连接分子，主要存在于非恶性胃上皮细胞中，在恶性转化过程中可进入肿瘤细胞表面，从而为癌症治疗提供了一个有吸引力的靶点。抗克劳丁 18.2 抗体唑贝妥昔单抗（zolbetuximab）的两项 III 期试验数据表明，克劳丁 18.2 阳性晚期胃癌是一个独立的治疗亚群，在化疗的基础上加用这种药物可使其获益。这一进展大大增加了符合靶向治疗条件的患者比例。此外，高亲和力单克隆抗体、双特异性抗体、嵌合抗原受体 T 细胞和具有旁观者杀伤效应的抗体-药物共轭物等新疗法已在表达 claudin 18.2 的胃癌患者中大显身手。这一新发展是药物开发人员超越传统靶点（如驱动基因改变或生长因子）的结果。在这篇综述中，我们将重点介绍针对晚期胃癌患者的claudin 18.2靶向疗法的生物学原理和临床活性，并探讨将claudin 18.2靶向疗法扩展到其他claudin 18.2阳性实体瘤患者的可能性。
{"title":"Claudin 18.2 as a novel therapeutic target","authors":"Izuma Nakayama, Changsong Qi, Yang Chen, Yoshiaki Nakamura, Lin Shen, Kohei Shitara","doi":"10.1038/s41571-024-00874-2","DOIUrl":"10.1038/s41571-024-00874-2","url":null,"abstract":"Claudin 18.2, a tight-junction molecule predominantly found in the nonmalignant gastric epithelium, becomes accessible on the tumour cell surface during malignant transformation, thereby providing an appealing target for cancer therapy. Data from two phase III trials testing the anti-claudin 18.2 antibody zolbetuximab have established claudin 18.2-positive advanced-stage gastric cancers as an independent therapeutic subset that derives benefit from the addition of this agent to chemotherapy. This development has substantially increased the percentage of patients eligible for targeted therapy. Furthermore, newer treatments, such as high-affinity monoclonal antibodies, bispecific antibodies, chimeric antigen receptor T cells and antibody–drug conjugates capable of bystander killing effects, have shown considerable promise in patients with claudin 18.2-expressing gastric cancers. This new development has resulted from drug developers moving beyond traditional targets, such as driver gene alterations or growth factors. In this Review, we highlight the biological rationale and explore the clinical activity of therapies that target claudin 18.2 in patients with advanced-stage gastric cancer and explore the potential for expansion of claudin 18.2-targeted therapies to patients with other claudin 18.2-positive solid tumours. The development and successful phase III testing of the anti-claudin 18.2 antibody zolbetuximab has provided a novel targeted therapy for the 30–40% of patients with strongly claudin 18.2-positive gastric cancers. Furthermore, the development of an effective targeted therapy for a target that does not have a driver role in cancer development provides a novel drug development paradigm. In this Review, the authors describe the development of claudin 18.2-targeted therapies, including zolbetuximab, as well as novel therapies, including chimeric antigen receptor (CAR) T cells, antibody–drug conjugates and bispecific antibodies, all of which have the potential to expand the number of patients who can derive benefit from claudin 18.2-targeted therapies in the near future.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140164995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-14DOI: 10.1038/s41571-024-00876-0
Daolin Tang, Guido Kroemer, Rui Kang
Copper, an essential trace element that exists in oxidized and reduced forms, has pivotal roles in a variety of biological processes, including redox chemistry, enzymatic reactions, mitochondrial respiration, iron metabolism, autophagy and immune modulation; maintaining copper homeostasis is crucial as both its deficiency and its excess are deleterious. Dysregulated copper metabolism has a dual role in tumorigenesis and cancer therapy. Specifically, cuproplasia describes copper-dependent cell growth and proliferation, including hyperplasia, metaplasia and neoplasia, whereas cuproptosis refers to a mitochondrial pathway of cell death triggered by excessive copper exposure and subsequent proteotoxic stress (although complex interactions between cuproptosis and other cell death mechanisms, such as ferroptosis, are likely and remain enigmatic). In this Review, we summarize advances in our understanding of copper metabolism, the molecular machineries underlying cuproplasia and cuproptosis, and their potential targeting for cancer therapy. These new findings advance the rapidly expanding field of translational cancer research focused on metal compounds. Copper is an essential trace element with inherent redox properties and fundamental roles in a diverse range of biological processes; therefore, maintaining copper homeostasis is crucial. In this Review, the authors discuss new insights into the mechanisms by which disrupted copper homeostasis contributes to tumour initiation and development, including the recently defined concepts of cuproplasia (copper-dependent cell growth and proliferation) and cuproptosis (a mitochondrial pathway of cell death triggered by excessive copper exposure). They also discuss potential strategies to exploit cuproplasia and cuproptosis for the treatment of cancer.
{"title":"Targeting cuproplasia and cuproptosis in cancer","authors":"Daolin Tang, Guido Kroemer, Rui Kang","doi":"10.1038/s41571-024-00876-0","DOIUrl":"10.1038/s41571-024-00876-0","url":null,"abstract":"Copper, an essential trace element that exists in oxidized and reduced forms, has pivotal roles in a variety of biological processes, including redox chemistry, enzymatic reactions, mitochondrial respiration, iron metabolism, autophagy and immune modulation; maintaining copper homeostasis is crucial as both its deficiency and its excess are deleterious. Dysregulated copper metabolism has a dual role in tumorigenesis and cancer therapy. Specifically, cuproplasia describes copper-dependent cell growth and proliferation, including hyperplasia, metaplasia and neoplasia, whereas cuproptosis refers to a mitochondrial pathway of cell death triggered by excessive copper exposure and subsequent proteotoxic stress (although complex interactions between cuproptosis and other cell death mechanisms, such as ferroptosis, are likely and remain enigmatic). In this Review, we summarize advances in our understanding of copper metabolism, the molecular machineries underlying cuproplasia and cuproptosis, and their potential targeting for cancer therapy. These new findings advance the rapidly expanding field of translational cancer research focused on metal compounds. Copper is an essential trace element with inherent redox properties and fundamental roles in a diverse range of biological processes; therefore, maintaining copper homeostasis is crucial. In this Review, the authors discuss new insights into the mechanisms by which disrupted copper homeostasis contributes to tumour initiation and development, including the recently defined concepts of cuproplasia (copper-dependent cell growth and proliferation) and cuproptosis (a mitochondrial pathway of cell death triggered by excessive copper exposure). They also discuss potential strategies to exploit cuproplasia and cuproptosis for the treatment of cancer.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140123906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-12DOI: 10.1038/s41571-024-00877-z
Despina Kontos
The benefits and potential harms of mammography-based screening for breast cancer are often a matter of debate. Here, I discuss the promises and limitations of a recent study that tested an artificial intelligence-based tool for the detection of breast cancer in digital mammograms in a large, prospective screening setting.
基于乳腺 X 射线照相术的乳腺癌筛查的益处和潜在危害经常引起争论。在此，我将讨论一项最新研究的前景和局限性，该研究测试了一种基于人工智能的工具，用于在大型前瞻性筛查环境中检测数字乳房X光照片中的乳腺癌。
{"title":"The promise of AI in personalized breast cancer screening: are we there yet?","authors":"Despina Kontos","doi":"10.1038/s41571-024-00877-z","DOIUrl":"10.1038/s41571-024-00877-z","url":null,"abstract":"The benefits and potential harms of mammography-based screening for breast cancer are often a matter of debate. Here, I discuss the promises and limitations of a recent study that tested an artificial intelligence-based tool for the detection of breast cancer in digital mammograms in a large, prospective screening setting.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140110885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-08DOI: 10.1038/s41571-024-00880-4
David Killock
{"title":"FIRSTMAPPP prospectively charts the efficacy of sunitinib for phaeochromocytoma and paraganglioma","authors":"David Killock","doi":"10.1038/s41571-024-00880-4","DOIUrl":"10.1038/s41571-024-00880-4","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-06DOI: 10.1038/s41571-024-00879-x
Diana Romero
{"title":"Non-inferiority of simple versus radical hysterectomy in low-risk cervical cancer","authors":"Diana Romero","doi":"10.1038/s41571-024-00879-x","DOIUrl":"10.1038/s41571-024-00879-x","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-29DOI: 10.1038/s41571-024-00869-z
Masuko Katoh, Yohann Loriot, Giovanni Brandi, Simona Tavolari, Zev A. Wainberg, Masaru Katoh
Fibroblast growth factor (FGF) signalling via FGF receptors (FGFR1–4) orchestrates fetal development and contributes to tissue and whole-body homeostasis, but can also promote tumorigenesis. Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. Erdafitinib is approved for patients with urothelial carcinoma harbouring FGFR2/3 alterations, and futibatinib and pemigatinib are approved for patients with cholangiocarcinoma harbouring FGFR2 fusions and/or rearrangements. Clinical benefit from these agents is in part limited by hyperphosphataemia owing to off-target inhibition of FGFR1 as well as the emergence of resistance mutations in FGFR genes, activation of bypass signalling pathways, concurrent TP53 alterations and possibly epithelial–mesenchymal transition-related isoform switching. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence. FGFR inhibitors are now approved for use in patients with advanced-stage urothelial carcinoma, cholangiocarcinoma and myeloid or lymphoid neoplasms that harbour certain FGFR alterations. Nonetheless, challenges such as tolerability and acquired resistance limit the clinical potential of these agents. In this Review, the authors summarize the available clinical data on FGFR inhibitors, describe promising novel agents and highlight future research directions that might optimize the efficacy of FGFR-targeted therapies.
{"title":"FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions","authors":"Masuko Katoh, Yohann Loriot, Giovanni Brandi, Simona Tavolari, Zev A. Wainberg, Masaru Katoh","doi":"10.1038/s41571-024-00869-z","DOIUrl":"10.1038/s41571-024-00869-z","url":null,"abstract":"Fibroblast growth factor (FGF) signalling via FGF receptors (FGFR1–4) orchestrates fetal development and contributes to tissue and whole-body homeostasis, but can also promote tumorigenesis. Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. Erdafitinib is approved for patients with urothelial carcinoma harbouring FGFR2/3 alterations, and futibatinib and pemigatinib are approved for patients with cholangiocarcinoma harbouring FGFR2 fusions and/or rearrangements. Clinical benefit from these agents is in part limited by hyperphosphataemia owing to off-target inhibition of FGFR1 as well as the emergence of resistance mutations in FGFR genes, activation of bypass signalling pathways, concurrent TP53 alterations and possibly epithelial–mesenchymal transition-related isoform switching. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence. FGFR inhibitors are now approved for use in patients with advanced-stage urothelial carcinoma, cholangiocarcinoma and myeloid or lymphoid neoplasms that harbour certain FGFR alterations. Nonetheless, challenges such as tolerability and acquired resistance limit the clinical potential of these agents. In this Review, the authors summarize the available clinical data on FGFR inhibitors, describe promising novel agents and highlight future research directions that might optimize the efficacy of FGFR-targeted therapies.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139996923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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