Pub Date : 2024-07-19DOI: 10.1038/s41571-024-00927-6
Niels W. C. J. van de Donk, Sonja Zweegman
BCMA-directed chimeric antigen receptor T cell therapies and bispecific T cell engagers are moving to earlier lines of therapy in multiple myeloma. In addition, combination therapy with the BCMA-targeting antibody–drug conjugate belantamab mafodotin at first or subsequent relapse has the potential to improve survival of patients with this disease. This increasing number of therapeutic options makes treatment selection and sequencing increasingly complex.
{"title":"BCMA-directed therapy for early relapsed and/or refractory multiple myeloma","authors":"Niels W. C. J. van de Donk, Sonja Zweegman","doi":"10.1038/s41571-024-00927-6","DOIUrl":"10.1038/s41571-024-00927-6","url":null,"abstract":"BCMA-directed chimeric antigen receptor T cell therapies and bispecific T cell engagers are moving to earlier lines of therapy in multiple myeloma. In addition, combination therapy with the BCMA-targeting antibody–drug conjugate belantamab mafodotin at first or subsequent relapse has the potential to improve survival of patients with this disease. This increasing number of therapeutic options makes treatment selection and sequencing increasingly complex.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"21 10","pages":"707-708"},"PeriodicalIF":81.1,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727582","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 : 2024-07-11DOI: 10.1038/s41571-024-00923-w
Duaa H. Al-Rawi, Emanuele Lettera, Jun Li, Melody DiBona, Samuel F. Bakhoum
Chromosomal instability (CIN) is a hallmark of cancer and a driver of metastatic dissemination, therapeutic resistance, and immune evasion. CIN is present in 60–80% of human cancers and poses a formidable therapeutic challenge as evidenced by the lack of clinically approved drugs that directly target CIN. This limitation in part reflects a lack of well-defined druggable targets as well as a dearth of tractable biomarkers enabling direct assessment and quantification of CIN in patients with cancer. Over the past decade, however, our understanding of the cellular mechanisms and consequences of CIN has greatly expanded, revealing novel therapeutic strategies for the treatment of chromosomally unstable tumours as well as new methods of assessing the dynamic nature of chromosome segregation errors that define CIN. In this Review, we describe advances that have shaped our understanding of CIN from a translational perspective, highlighting both challenges and opportunities in the development of therapeutic interventions for patients with chromosomally unstable cancers. Chromosomal instability (CIN) is a dynamic phenotype characterized by changes in chromosome number and structure and is a hallmark of clinically aggressive malignancies. Nonetheless, the ability of cancer cells to tolerate CIN creates several potential therapeutic vulnerabilities. In this Review, the authors describe the development of CIN and how this phenotype promotes carcinogenesis and tumour progression as well as describing the various attempts to develop targeted therapies based on the specific vulnerabilities of these tumours.
{"title":"Targeting chromosomal instability in patients with cancer","authors":"Duaa H. Al-Rawi, Emanuele Lettera, Jun Li, Melody DiBona, Samuel F. Bakhoum","doi":"10.1038/s41571-024-00923-w","DOIUrl":"10.1038/s41571-024-00923-w","url":null,"abstract":"Chromosomal instability (CIN) is a hallmark of cancer and a driver of metastatic dissemination, therapeutic resistance, and immune evasion. CIN is present in 60–80% of human cancers and poses a formidable therapeutic challenge as evidenced by the lack of clinically approved drugs that directly target CIN. This limitation in part reflects a lack of well-defined druggable targets as well as a dearth of tractable biomarkers enabling direct assessment and quantification of CIN in patients with cancer. Over the past decade, however, our understanding of the cellular mechanisms and consequences of CIN has greatly expanded, revealing novel therapeutic strategies for the treatment of chromosomally unstable tumours as well as new methods of assessing the dynamic nature of chromosome segregation errors that define CIN. In this Review, we describe advances that have shaped our understanding of CIN from a translational perspective, highlighting both challenges and opportunities in the development of therapeutic interventions for patients with chromosomally unstable cancers. Chromosomal instability (CIN) is a dynamic phenotype characterized by changes in chromosome number and structure and is a hallmark of clinically aggressive malignancies. Nonetheless, the ability of cancer cells to tolerate CIN creates several potential therapeutic vulnerabilities. In this Review, the authors describe the development of CIN and how this phenotype promotes carcinogenesis and tumour progression as well as describing the various attempts to develop targeted therapies based on the specific vulnerabilities of these tumours.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"21 9","pages":"645-659"},"PeriodicalIF":81.1,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141584529","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 : 2024-07-09DOI: 10.1038/s41571-024-00925-8
Jonathan Strosberg, Mauro Cives
The NETTER-2 trial provides the first phase III evidence that 177Lu-dotatate is active as first-line therapy in patients with gastroenteropancreatic neuroendocrine tumours with a Ki-67 proliferative index of 10–55%. This approach is an important addition to the first-line therapeutic armamentarium, although treatment selection based on patient-specific and tumour-specific characteristics remains appropriate.
{"title":"Is NETTER-2 a practice-changing trial?","authors":"Jonathan Strosberg, Mauro Cives","doi":"10.1038/s41571-024-00925-8","DOIUrl":"10.1038/s41571-024-00925-8","url":null,"abstract":"The NETTER-2 trial provides the first phase III evidence that 177Lu-dotatate is active as first-line therapy in patients with gastroenteropancreatic neuroendocrine tumours with a Ki-67 proliferative index of 10–55%. This approach is an important addition to the first-line therapeutic armamentarium, although treatment selection based on patient-specific and tumour-specific characteristics remains appropriate.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"21 10","pages":"705-706"},"PeriodicalIF":81.1,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561413","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 : 2024-07-04DOI: 10.1038/s41571-024-00914-x
Triparna Sen, Nobuyuki Takahashi, Subhamoy Chakraborty, Naoko Takebe, Amin H. Nassar, Nagla A. Karim, Sonam Puri, Abdul Rafeh Naqash
Small-cell lung cancer (SCLC) has traditionally been considered a recalcitrant cancer with a dismal prognosis, with only modest advances in therapeutic strategies over the past several decades. Comprehensive genomic assessments of SCLC have revealed that most of these tumours harbour deletions of the tumour-suppressor genes TP53 and RB1 but, in contrast to non-small-cell lung cancer, have failed to identify targetable alterations. The expression status of four transcription factors with key roles in SCLC pathogenesis defines distinct molecular subtypes of the disease, potentially enabling specific therapeutic approaches. Overexpression and amplification of MYC paralogues also affect the biology and therapeutic vulnerabilities of SCLC. Several other attractive targets have emerged in the past few years, including inhibitors of DNA-damage-response pathways, epigenetic modifiers, antibody–drug conjugates and chimeric antigen receptor T cells. However, the rapid development of therapeutic resistance and lack of biomarkers for effective selection of patients with SCLC are ongoing challenges. Emerging single-cell RNA sequencing data are providing insights into the plasticity and intratumoural and intertumoural heterogeneity of SCLC that might be associated with therapeutic resistance. In this Review, we provide a comprehensive overview of the latest advances in genomic and transcriptomic characterization of SCLC with a particular focus on opportunities for translation into new therapeutic approaches to improve patient outcomes. Traditionally, patients with small-cell lung cancer (SCLC), a malignancy with a dismal prognosis, have had limited treatment options. Over the past few years, advances in the molecular characterization of SCLC have revealed novel therapeutic targets. The authors of this Review summarize these findings and discuss emerging opportunities and challenges for their translation into new treatment approaches.
{"title":"Emerging advances in defining the molecular and therapeutic landscape of small-cell lung cancer","authors":"Triparna Sen, Nobuyuki Takahashi, Subhamoy Chakraborty, Naoko Takebe, Amin H. Nassar, Nagla A. Karim, Sonam Puri, Abdul Rafeh Naqash","doi":"10.1038/s41571-024-00914-x","DOIUrl":"10.1038/s41571-024-00914-x","url":null,"abstract":"Small-cell lung cancer (SCLC) has traditionally been considered a recalcitrant cancer with a dismal prognosis, with only modest advances in therapeutic strategies over the past several decades. Comprehensive genomic assessments of SCLC have revealed that most of these tumours harbour deletions of the tumour-suppressor genes TP53 and RB1 but, in contrast to non-small-cell lung cancer, have failed to identify targetable alterations. The expression status of four transcription factors with key roles in SCLC pathogenesis defines distinct molecular subtypes of the disease, potentially enabling specific therapeutic approaches. Overexpression and amplification of MYC paralogues also affect the biology and therapeutic vulnerabilities of SCLC. Several other attractive targets have emerged in the past few years, including inhibitors of DNA-damage-response pathways, epigenetic modifiers, antibody–drug conjugates and chimeric antigen receptor T cells. However, the rapid development of therapeutic resistance and lack of biomarkers for effective selection of patients with SCLC are ongoing challenges. Emerging single-cell RNA sequencing data are providing insights into the plasticity and intratumoural and intertumoural heterogeneity of SCLC that might be associated with therapeutic resistance. In this Review, we provide a comprehensive overview of the latest advances in genomic and transcriptomic characterization of SCLC with a particular focus on opportunities for translation into new therapeutic approaches to improve patient outcomes. Traditionally, patients with small-cell lung cancer (SCLC), a malignancy with a dismal prognosis, have had limited treatment options. Over the past few years, advances in the molecular characterization of SCLC have revealed novel therapeutic targets. The authors of this Review summarize these findings and discuss emerging opportunities and challenges for their translation into new treatment approaches.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"21 8","pages":"610-627"},"PeriodicalIF":81.1,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534885","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 : 2024-07-03DOI: 10.1038/s41571-024-00913-y
Paola Neri, Noémie Leblay, Holly Lee, Annamaria Gulla, Nizar J. Bahlis, Kenneth C. Anderson
A better understanding of the roles of the adaptive and innate immune systems in the oncogenesis of cancers including multiple myeloma (MM) has led to the development of novel immune-based therapies. B cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D) and Fc receptor-like protein 5 (FcRL5, also known as FcRH5) are cell-surface transmembrane proteins expressed by plasma cells, and have been identified as prominent immunotherapeutic targets in MM, with promising activity demonstrated in patients with heavily pretreated relapsed and/or refractory disease. Indeed, since 2020, antibody–drug conjugates, bispecific T cell engagers and autologous chimeric antigen receptor T cells targeting BCMA or GPRC5D have been approved for the treatment of relapsed and/or refractory MM. However, responses to these therapies are not universal, and acquired resistance invariably occurs. In this Review, we discuss the various immunotherapeutic approaches targeting BCMA, GPRC5D and FcRL5 that are currently either available or in clinical development for patients with MM. We also review the mechanisms underlying resistance to such therapies, and discuss potential strategies to overcome these mechanisms and improve patient outcomes. Novel immunotherapeutic strategies based on targeting specific tumour-associated antigens with antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BTEs) are revolutionizing the treatment of multiple myeloma. In this Review, the authors describe the clinical experience to date with ADCs, CAR T cells and BTEs targeting B cell maturation antigen, G protein-coupled receptor family C group 5 member D and Fc receptor-like protein 5. In addition, they discuss the mechanisms of resistance to such therapies, and potential strategies by which resistance could be overcome to improve patient outcomes.
{"title":"Just scratching the surface: novel treatment approaches for multiple myeloma targeting cell membrane proteins","authors":"Paola Neri, Noémie Leblay, Holly Lee, Annamaria Gulla, Nizar J. Bahlis, Kenneth C. Anderson","doi":"10.1038/s41571-024-00913-y","DOIUrl":"10.1038/s41571-024-00913-y","url":null,"abstract":"A better understanding of the roles of the adaptive and innate immune systems in the oncogenesis of cancers including multiple myeloma (MM) has led to the development of novel immune-based therapies. B cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D) and Fc receptor-like protein 5 (FcRL5, also known as FcRH5) are cell-surface transmembrane proteins expressed by plasma cells, and have been identified as prominent immunotherapeutic targets in MM, with promising activity demonstrated in patients with heavily pretreated relapsed and/or refractory disease. Indeed, since 2020, antibody–drug conjugates, bispecific T cell engagers and autologous chimeric antigen receptor T cells targeting BCMA or GPRC5D have been approved for the treatment of relapsed and/or refractory MM. However, responses to these therapies are not universal, and acquired resistance invariably occurs. In this Review, we discuss the various immunotherapeutic approaches targeting BCMA, GPRC5D and FcRL5 that are currently either available or in clinical development for patients with MM. We also review the mechanisms underlying resistance to such therapies, and discuss potential strategies to overcome these mechanisms and improve patient outcomes. Novel immunotherapeutic strategies based on targeting specific tumour-associated antigens with antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BTEs) are revolutionizing the treatment of multiple myeloma. In this Review, the authors describe the clinical experience to date with ADCs, CAR T cells and BTEs targeting B cell maturation antigen, G protein-coupled receptor family C group 5 member D and Fc receptor-like protein 5. In addition, they discuss the mechanisms of resistance to such therapies, and potential strategies by which resistance could be overcome to improve patient outcomes.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"21 8","pages":"590-609"},"PeriodicalIF":81.1,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498553","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 : 2024-06-25DOI: 10.1038/s41571-024-00919-6
Diana Romero
{"title":"Asciminib is safe and effective in patients with newly diagnosed CML","authors":"Diana Romero","doi":"10.1038/s41571-024-00919-6","DOIUrl":"10.1038/s41571-024-00919-6","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"21 8","pages":"566-566"},"PeriodicalIF":81.1,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450979","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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