Pub Date : 2024-01-12DOI: 10.1146/annurev-cancerbio-062722-012209
Huarui Cui, Morgan Stilgenbauer, Angela N. Koehler
Dysregulated transcription factor activity is a defining feature of various cancer types. As such, targeting oncogenic transcriptional dependency has long been pursued as a potential therapeutic approach. However, transcription factors have historically been deemed as undruggable targets due to their highly disordered structures and lack of well-defined binding pockets. Nevertheless, interest in their pharmacologic inhibition and destruction has not dwindled in recent years. Here, we discuss new small-molecule-based approaches to target various transcription factors. Ligands with different mechanisms of action, such as inhibitors, molecular glue degraders, and proteolysis targeting chimeras, have recently seen success preclinically and clinically. We review how these strategies overcome the challenges presented by targeting transcription factors.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Small-Molecule Approaches to Target Transcription Factors","authors":"Huarui Cui, Morgan Stilgenbauer, Angela N. Koehler","doi":"10.1146/annurev-cancerbio-062722-012209","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062722-012209","url":null,"abstract":"Dysregulated transcription factor activity is a defining feature of various cancer types. As such, targeting oncogenic transcriptional dependency has long been pursued as a potential therapeutic approach. However, transcription factors have historically been deemed as undruggable targets due to their highly disordered structures and lack of well-defined binding pockets. Nevertheless, interest in their pharmacologic inhibition and destruction has not dwindled in recent years. Here, we discuss new small-molecule-based approaches to target various transcription factors. Ligands with different mechanisms of action, such as inhibitors, molecular glue degraders, and proteolysis targeting chimeras, have recently seen success preclinically and clinically. We review how these strategies overcome the challenges presented by targeting transcription factors.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":"113 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139462118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-11DOI: 10.1146/annurev-cancerbio-061421-014236
Erin W. Meermeier, P. L. Bergsagel, M. Chesi
Recent therapeutic advances have significantly improved the outcome for patients with multiple myeloma (MM). The backbone of successful standard therapy is the combination of ikaros degraders, glucocorticoids, and proteasome inhibitors that interfere with the integrity of myeloma-specific superenhancers by directly or indirectly targeting enhancer-bound transcription factors and coactivators that control expression of MM dependency genes. T cell engagers and chimeric antigen receptor T cells redirect patients’ own T cells onto defined tumor antigens to kill MM cells. They have induced complete remissions even in end-stage patients. Unfortunately, responses to both conventional therapy and immunotherapy are not durable, and tumor heterogeneity, antigen loss, and lack of T cell fitness lead to therapy resistance and relapse. Novel approaches are under development to target myeloma-specific vulnerabilities, as is the design of multimodality immunological approaches, including and beyond T cells, that simultaneously recognize multiple epitopes to prevent antigen escape and tumor relapse. Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
最近的治疗进展大大改善了多发性骨髓瘤（MM）患者的预后。成功的标准疗法的支柱是结合使用 ikaros 降解剂、糖皮质激素和蛋白酶体抑制剂，通过直接或间接靶向增强子结合的转录因子和控制 MM 依赖基因表达的辅助激活因子，干扰骨髓瘤特异性超增强子的完整性。T 细胞吞噬因子和嵌合抗原受体 T 细胞可将患者自身的 T 细胞重新定向到确定的肿瘤抗原上，从而杀死 MM 细胞。它们甚至能使晚期患者的病情完全缓解。遗憾的是，对传统疗法和免疫疗法的反应并不持久，肿瘤的异质性、抗原丢失和T细胞的缺乏导致耐药和复发。目前正在开发针对骨髓瘤特异性弱点的新方法，以及设计同时识别多个表位以防止抗原逃逸和肿瘤复发的多模式免疫方法，包括T细胞和T细胞以外的免疫方法。癌症生物学年刊》（Annual Review of Cancer Biology）第8卷的最终在线出版日期预计为2024年4月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
{"title":"Next-Generation Therapies for Multiple Myeloma","authors":"Erin W. Meermeier, P. L. Bergsagel, M. Chesi","doi":"10.1146/annurev-cancerbio-061421-014236","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061421-014236","url":null,"abstract":"Recent therapeutic advances have significantly improved the outcome for patients with multiple myeloma (MM). The backbone of successful standard therapy is the combination of ikaros degraders, glucocorticoids, and proteasome inhibitors that interfere with the integrity of myeloma-specific superenhancers by directly or indirectly targeting enhancer-bound transcription factors and coactivators that control expression of MM dependency genes. T cell engagers and chimeric antigen receptor T cells redirect patients’ own T cells onto defined tumor antigens to kill MM cells. They have induced complete remissions even in end-stage patients. Unfortunately, responses to both conventional therapy and immunotherapy are not durable, and tumor heterogeneity, antigen loss, and lack of T cell fitness lead to therapy resistance and relapse. Novel approaches are under development to target myeloma-specific vulnerabilities, as is the design of multimodality immunological approaches, including and beyond T cells, that simultaneously recognize multiple epitopes to prevent antigen escape and tumor relapse. Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":"9 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139438800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-02DOI: 10.1146/annurev-cancerbio-062822-010523
Mohamed Omar, Mohammad K. Alexanderani, Itzel Valencia, Massimo Loda, Luigi Marchionni
Digital pathology, powered by whole-slide imaging technology, has the potential to transform the landscape of cancer research and diagnosis. By converting traditional histopathological specimens into high-resolution digital images, it paves the way for computer-aided analysis, uncovering a new horizon for the integration of artificial intelligence (AI) and machine learning (ML). The accuracy of AI- and ML-driven tools in distinguishing benign from malignant tumors and predicting patient outcomes has ushered in an era of unprecedented opportunities in cancer care. However, this promising field also presents substantial challenges, such as data security, ethical considerations, and the need for standardization. In this review, we delve into the needs that digital pathology addresses in cancer research, the opportunities it presents, its inherent potential, and the challenges it faces. The goal of this review is to stimulate a comprehensive discourse on harnessing digital pathology and AI in health care, with an emphasis on cancer diagnosis and research.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
由全切片成像技术驱动的数字病理学有可能改变癌症研究和诊断的格局。通过将传统的组织病理学标本转化为高分辨率数字图像，它为计算机辅助分析铺平了道路，为人工智能（AI）和机器学习（ML）的整合开辟了新天地。人工智能和 ML 驱动的工具在区分良性和恶性肿瘤以及预测患者预后方面的准确性为癌症治疗带来了前所未有的机遇。然而，这一前景广阔的领域也面临着巨大的挑战，如数据安全、伦理考虑和标准化需求。在这篇综述中，我们将深入探讨数字病理学在癌症研究中的需求、它带来的机遇、内在潜力以及面临的挑战。这篇综述的目的是激发关于在医疗保健中利用数字病理学和人工智能的全面讨论，重点是癌症诊断和研究。《癌症生物学年度综述》第8卷的最终在线出版日期预计为2024年4月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
{"title":"Applications of Digital Pathology in Cancer: A Comprehensive Review","authors":"Mohamed Omar, Mohammad K. Alexanderani, Itzel Valencia, Massimo Loda, Luigi Marchionni","doi":"10.1146/annurev-cancerbio-062822-010523","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-010523","url":null,"abstract":"Digital pathology, powered by whole-slide imaging technology, has the potential to transform the landscape of cancer research and diagnosis. By converting traditional histopathological specimens into high-resolution digital images, it paves the way for computer-aided analysis, uncovering a new horizon for the integration of artificial intelligence (AI) and machine learning (ML). The accuracy of AI- and ML-driven tools in distinguishing benign from malignant tumors and predicting patient outcomes has ushered in an era of unprecedented opportunities in cancer care. However, this promising field also presents substantial challenges, such as data security, ethical considerations, and the need for standardization. In this review, we delve into the needs that digital pathology addresses in cancer research, the opportunities it presents, its inherent potential, and the challenges it faces. The goal of this review is to stimulate a comprehensive discourse on harnessing digital pathology and AI in health care, with an emphasis on cancer diagnosis and research.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":"33 4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139084612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-02DOI: 10.1146/annurev-cancerbio-062822-021934
Pablo R. Freire, Jevon A. Cutler, Scott A. Armstrong
The direct targeting of chromatin-associated proteins is increasingly recognized as a potential therapeutic strategy for the treatment of cancer. In this review, we discuss a prominent example, namely, small-molecule inhibitors that target the menin–KMT2A interaction. These molecules are currently being investigated in clinical trials and showing significant promise. We describe the unique specificity of menin–KMT2A protein complexes for the transcriptional regulation of a small subset of genes that drive developmental and leukemic gene expression. We review the chromatin-associated KMT2A complex and the protein–protein interaction between menin and KMT2A that is essential for the maintenance of different types of cancer cells, but most notably acute myeloid leukemia (AML). We also summarize the development of menin inhibitors and their effects on chromatin. Finally, we discuss the promising early results from clinical trials in patients with AML and the recent discovery of therapy-resistant menin mutants that validate menin as a therapeutic target but also may present therapeutic challenges.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Therapeutic Targeting of the Menin–KMT2A Interaction","authors":"Pablo R. Freire, Jevon A. Cutler, Scott A. Armstrong","doi":"10.1146/annurev-cancerbio-062822-021934","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-021934","url":null,"abstract":"The direct targeting of chromatin-associated proteins is increasingly recognized as a potential therapeutic strategy for the treatment of cancer. In this review, we discuss a prominent example, namely, small-molecule inhibitors that target the menin–KMT2A interaction. These molecules are currently being investigated in clinical trials and showing significant promise. We describe the unique specificity of menin–KMT2A protein complexes for the transcriptional regulation of a small subset of genes that drive developmental and leukemic gene expression. We review the chromatin-associated KMT2A complex and the protein–protein interaction between menin and KMT2A that is essential for the maintenance of different types of cancer cells, but most notably acute myeloid leukemia (AML). We also summarize the development of menin inhibitors and their effects on chromatin. Finally, we discuss the promising early results from clinical trials in patients with AML and the recent discovery of therapy-resistant menin mutants that validate menin as a therapeutic target but also may present therapeutic challenges.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139084371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-18DOI: 10.1146/annurev-cancerbio-062822-023316
Barbra Johnson Sasu, Elvin James Lauron, Thomas Schulz, Hsin-Yuan Cheng, Cesar Sommer
Autologous chimeric antigen receptor (CAR) T cell therapy, produced from the patient's own T cells, has changed the treatment landscape for hematologic malignancies but has some drawbacks that prevent large-scale clinical application, including logistical complexities in supply, patient T cell health, treatment delays, and limited manufacturing slots. Allogeneic, or off-the-shelf, CAR T cell therapies have the potential to overcome many of the limitations of autologous therapies, with the aim of bringing benefit to all patients eligible for treatment. This review highlights the progress and challenges of allogeneic cell therapies for cancer and the various approaches that are being evaluated preclinically and in clinical trials to enhance the persistence and antitumor efficacy of allogeneic CAR T cells, including new strategies to avoid immune rejection.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
自体嵌合抗原受体（CAR）T细胞疗法是由患者自身的T细胞产生的，它改变了血液系统恶性肿瘤的治疗格局，但也存在一些弊端，阻碍了大规模临床应用，包括供应方面的物流复杂性、患者T细胞的健康状况、治疗延迟以及生产名额有限。异体 CAR T 细胞疗法或现成的 CAR T 细胞疗法有可能克服自体疗法的许多局限性，为所有符合治疗条件的患者带来益处。这篇综述重点介绍了癌症异体细胞疗法的进展和挑战，以及为提高异体CAR T细胞的持久性和抗肿瘤疗效而在临床前和临床试验中评估的各种方法，包括避免免疫排斥的新策略。《癌症生物学年度综述》第8卷的最终在线出版日期预计为2024年4月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
{"title":"Allogeneic CAR T Cell Therapy for Cancer","authors":"Barbra Johnson Sasu, Elvin James Lauron, Thomas Schulz, Hsin-Yuan Cheng, Cesar Sommer","doi":"10.1146/annurev-cancerbio-062822-023316","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-023316","url":null,"abstract":"Autologous chimeric antigen receptor (CAR) T cell therapy, produced from the patient's own T cells, has changed the treatment landscape for hematologic malignancies but has some drawbacks that prevent large-scale clinical application, including logistical complexities in supply, patient T cell health, treatment delays, and limited manufacturing slots. Allogeneic, or off-the-shelf, CAR T cell therapies have the potential to overcome many of the limitations of autologous therapies, with the aim of bringing benefit to all patients eligible for treatment. This review highlights the progress and challenges of allogeneic cell therapies for cancer and the various approaches that are being evaluated preclinically and in clinical trials to enhance the persistence and antitumor efficacy of allogeneic CAR T cells, including new strategies to avoid immune rejection.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138744321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-18DOI: 10.1146/annurev-cancerbio-062722-034650
Antonella De Cola, Amelia Foss, Richard Gilbertson, Manav Pathania
Pediatric brain tumors comprise a diverse set of diseases. (Epi)genomic analyses have provided insights into the biology of these tumors, stratifying them into distinct subtypes with different oncogenic driver mechanisms and developmental origins. A feature shared by these tumors is their initiation within neural stem or progenitor cells that undergo stalled differentiation in unique, niche-dependent ways. In this review, we provide an overview of how (epi)genomic characterization has revealed pediatric brain tumor origins and underlying biology. We focus on the best characterized tumor types—gliomas, ependymomas, medulloblastomas—as well as select rarer types such as embryonal tumors with multilayered rosettes, atypical teratoid/rhabdoid tumors, and choroid plexus carcinomas in which new insights have been made. The discovery of diverse developmental origins of these tumors and their defining molecular characteristics has led to a better understanding of their etiologies, with important implications for diagnostics, future therapy development, and clinical trial design.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Biological, Diagnostic, and Therapeutic Insights from (Epi)Genomic Profiling of Pediatric Brain Tumors","authors":"Antonella De Cola, Amelia Foss, Richard Gilbertson, Manav Pathania","doi":"10.1146/annurev-cancerbio-062722-034650","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062722-034650","url":null,"abstract":"Pediatric brain tumors comprise a diverse set of diseases. (Epi)genomic analyses have provided insights into the biology of these tumors, stratifying them into distinct subtypes with different oncogenic driver mechanisms and developmental origins. A feature shared by these tumors is their initiation within neural stem or progenitor cells that undergo stalled differentiation in unique, niche-dependent ways. In this review, we provide an overview of how (epi)genomic characterization has revealed pediatric brain tumor origins and underlying biology. We focus on the best characterized tumor types—gliomas, ependymomas, medulloblastomas—as well as select rarer types such as embryonal tumors with multilayered rosettes, atypical teratoid/rhabdoid tumors, and choroid plexus carcinomas in which new insights have been made. The discovery of diverse developmental origins of these tumors and their defining molecular characteristics has led to a better understanding of their etiologies, with important implications for diagnostics, future therapy development, and clinical trial design.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138744263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-18DOI: 10.1146/annurev-cancerbio-062822-123558
Gianna Maggiore, Hao Zhu
Regeneration and cancer share genetic mechanisms and cellular processes. While highly regenerative cells are often the source of cancer, persistent injury or imperfect regeneration in the form of wound healing can lead to degenerative conditions that favor cancer development. Thus, the causal interplay between regeneration and cancer is complex. This article focuses on understanding how functional variation in regeneration and wound healing might influence the risk of cancer. Variation in regenerative capacity might create trade-offs or adaptations that significantly alter cancer risk. From this perspective, we probe the causal relationships between regeneration, wound healing, and cancer.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
再生和癌症共享遗传机制和细胞过程。再生能力强的细胞往往是癌症的源头，而持续的损伤或伤口愈合形式的不完善再生会导致退行性病变，从而有利于癌症的发展。因此，再生与癌症之间的因果关系非常复杂。本文重点探讨再生和伤口愈合的功能变异如何影响癌症风险。再生能力的差异可能会产生权衡或适应，从而显著改变癌症风险。从这个角度出发，我们探究了再生、伤口愈合和癌症之间的因果关系。《癌症生物学年刊》（Annual Review of Cancer Biology）第8卷的最终在线出版日期预计为2024年4月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
{"title":"Relationships Between Regeneration, Wound Healing, and Cancer","authors":"Gianna Maggiore, Hao Zhu","doi":"10.1146/annurev-cancerbio-062822-123558","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-123558","url":null,"abstract":"Regeneration and cancer share genetic mechanisms and cellular processes. While highly regenerative cells are often the source of cancer, persistent injury or imperfect regeneration in the form of wound healing can lead to degenerative conditions that favor cancer development. Thus, the causal interplay between regeneration and cancer is complex. This article focuses on understanding how functional variation in regeneration and wound healing might influence the risk of cancer. Variation in regenerative capacity might create trade-offs or adaptations that significantly alter cancer risk. From this perspective, we probe the causal relationships between regeneration, wound healing, and cancer.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138744173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-15DOI: 10.1146/annurev-cancerbio-070620-092730
Ellis J. Curtis, John C. Rose, Paul S. Mischel, Howard Y. Chang
In cancer, oncogenes can untether themselves from chromosomes onto circular, extrachromosomal DNA (ecDNA) particles. ecDNA are common in many of the most aggressive forms of cancer of women and men and of adults and children, and they contribute to treatment resistance and shorter survival for patients. Hiding in plain sight and missing from cancer genome maps, ecDNA was not, until recently, widely recognized to be an important feature of cancer pathogenesis. However, extensive new data demonstrate that ecDNA is a frequent and potent driver of aggressive cancer growth and treatment failure that can arise early or late in the course of the disease. The non-Mendelian genetics of ecDNA lies at the heart of the problem. By untethering themselves from chromosomes, ecDNA are randomly distributed to daughter cells during cell division, promoting high oncogene copy number, intratumoral genetic heterogeneity, accelerated tumor evolution, and treatment resistance due to rapid genome change. Further, the circular shape of ecDNA, and its high level of chromatin accessibility, promotes oncogene transcription and generates unique enhancer–promoter interactions in cis, as well as cooperative regulatory interactions between ecDNA particles in trans. In this review, we discuss the state of the field and its implications for patients with oncogene-amplified cancers.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Extrachromosomal DNA: Biogenesis and Functions in Cancer","authors":"Ellis J. Curtis, John C. Rose, Paul S. Mischel, Howard Y. Chang","doi":"10.1146/annurev-cancerbio-070620-092730","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-070620-092730","url":null,"abstract":"In cancer, oncogenes can untether themselves from chromosomes onto circular, extrachromosomal DNA (ecDNA) particles. ecDNA are common in many of the most aggressive forms of cancer of women and men and of adults and children, and they contribute to treatment resistance and shorter survival for patients. Hiding in plain sight and missing from cancer genome maps, ecDNA was not, until recently, widely recognized to be an important feature of cancer pathogenesis. However, extensive new data demonstrate that ecDNA is a frequent and potent driver of aggressive cancer growth and treatment failure that can arise early or late in the course of the disease. The non-Mendelian genetics of ecDNA lies at the heart of the problem. By untethering themselves from chromosomes, ecDNA are randomly distributed to daughter cells during cell division, promoting high oncogene copy number, intratumoral genetic heterogeneity, accelerated tumor evolution, and treatment resistance due to rapid genome change. Further, the circular shape of ecDNA, and its high level of chromatin accessibility, promotes oncogene transcription and generates unique enhancer–promoter interactions in cis, as well as cooperative regulatory interactions between ecDNA particles in trans. In this review, we discuss the state of the field and its implications for patients with oncogene-amplified cancers.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138692417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-06DOI: 10.1146/annurev-cancerbio-061421-012927
Yonina R. Murciano-Goroff, Manik Uppal, Monica Chen, Guilherme Harada, Alison M. Schram
Large-scale tumor molecular profiling has revealed that diverse cancer histologies are driven by common pathways with unifying biomarkers that can be exploited therapeutically. Disease-agnostic basket trials have been increasingly utilized to test biomarker-driven therapies across cancer types. These trials have led to drug approvals and improved the lives of patients while simultaneously advancing our understanding of cancer biology. This review focuses on the practicalities of implementing basket trials, with an emphasis on molecularly targeted trials. We examine the biologic subtleties of genomic biomarker and patient selection, discuss previous successes in drug development facilitated by basket trials, describe certain novel targets and drugs, and emphasize practical considerations for participant recruitment and study design. This review also highlights strategies for aiding patient access to basket trials. As basket trials become more common, steps to ensure equitable implementation of these studies will be critical for molecularly targeted drug development.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Basket Trials: Past, Present, and Future","authors":"Yonina R. Murciano-Goroff, Manik Uppal, Monica Chen, Guilherme Harada, Alison M. Schram","doi":"10.1146/annurev-cancerbio-061421-012927","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061421-012927","url":null,"abstract":"Large-scale tumor molecular profiling has revealed that diverse cancer histologies are driven by common pathways with unifying biomarkers that can be exploited therapeutically. Disease-agnostic basket trials have been increasingly utilized to test biomarker-driven therapies across cancer types. These trials have led to drug approvals and improved the lives of patients while simultaneously advancing our understanding of cancer biology. This review focuses on the practicalities of implementing basket trials, with an emphasis on molecularly targeted trials. We examine the biologic subtleties of genomic biomarker and patient selection, discuss previous successes in drug development facilitated by basket trials, describe certain novel targets and drugs, and emphasize practical considerations for participant recruitment and study design. This review also highlights strategies for aiding patient access to basket trials. As basket trials become more common, steps to ensure equitable implementation of these studies will be critical for molecularly targeted drug development.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138534860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-06DOI: 10.1146/annurev-cancerbio-061521-093717
Jane A. Healy, Jin-Hwan Han, David Bauché, Tanya E. Keenan, Jose Casasnovas-Nieves, Konstantin Dobrenkov
Progress in our understanding of how tumor cells co-opt immune checkpoint receptor (ICR) regulation of the immune response to suppress T cell function and how these proteins interact in the tumor microenvironment has resulted in the development of a plethora of therapeutic ICR monoclonal antibodies. While anti-CTLA-4 and anti-PD-1/PD-L1 therapies have provided meaningful clinical benefit in patients with certain cancers, many patients either do not respond or experience disease progression. As such, dual blockade of PD-1/PD-L1 and ICRs with alternative mechanisms of action has the potential to improve outcomes in patients with cancer. In this review, we focus on the biology of and clinical investigations into two promising ICR targets: LAG-3 and TIGIT. The data suggest that blockade of these ICRs in combination with PD-1/PD-L1 in immune-sensitive tumors could enhance anti-PD-1 efficacy without increased toxicity, facilitate combinations with standard-of-care therapies, and extend treatment benefit to more patients.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Advances in Therapies Targeting Inhibitory Checkpoint Receptors: TIGIT, LAG-3, and Beyond","authors":"Jane A. Healy, Jin-Hwan Han, David Bauché, Tanya E. Keenan, Jose Casasnovas-Nieves, Konstantin Dobrenkov","doi":"10.1146/annurev-cancerbio-061521-093717","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061521-093717","url":null,"abstract":"Progress in our understanding of how tumor cells co-opt immune checkpoint receptor (ICR) regulation of the immune response to suppress T cell function and how these proteins interact in the tumor microenvironment has resulted in the development of a plethora of therapeutic ICR monoclonal antibodies. While anti-CTLA-4 and anti-PD-1/PD-L1 therapies have provided meaningful clinical benefit in patients with certain cancers, many patients either do not respond or experience disease progression. As such, dual blockade of PD-1/PD-L1 and ICRs with alternative mechanisms of action has the potential to improve outcomes in patients with cancer. In this review, we focus on the biology of and clinical investigations into two promising ICR targets: LAG-3 and TIGIT. The data suggest that blockade of these ICRs in combination with PD-1/PD-L1 in immune-sensitive tumors could enhance anti-PD-1 efficacy without increased toxicity, facilitate combinations with standard-of-care therapies, and extend treatment benefit to more patients.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138534864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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