Pub Date : 2024-06-18DOI: 10.1146/annurev-cancerbio-062822-112257
Yogameenakshi Haribabu, Emma Bhote, Lucy A. Godley
Deleterious germline variants are now recognized as common drivers of hematopoietic malignancies (HMs) and bone marrow failure syndromes. With the increasing use of personalized medicine and the application of tumor-based profiling via next-generation sequencing, diagnosis of HM predisposition occurs with increasing frequency. Although deleterious germline variants can be readily identified by comprehensive clinical testing, numerous barriers exist for many clinicians. Observations regarding particular germline predisposition disorders challenge widely held assumptions about these conditions. Here, we review approaches to germline genetic testing, highlighting key points in a typical patient's course that present challenges for testing and interpreting results. Increasing awareness by health care providers of these conditions and improvements in testing platforms are crucial for enabling a proactive approach to tailoring a suitable treatment plan and surveillance program for the patient and their family members.
{"title":"Germline Predisposition to Hematopoietic Malignancies: An Overview","authors":"Yogameenakshi Haribabu, Emma Bhote, Lucy A. Godley","doi":"10.1146/annurev-cancerbio-062822-112257","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-112257","url":null,"abstract":"Deleterious germline variants are now recognized as common drivers of hematopoietic malignancies (HMs) and bone marrow failure syndromes. With the increasing use of personalized medicine and the application of tumor-based profiling via next-generation sequencing, diagnosis of HM predisposition occurs with increasing frequency. Although deleterious germline variants can be readily identified by comprehensive clinical testing, numerous barriers exist for many clinicians. Observations regarding particular germline predisposition disorders challenge widely held assumptions about these conditions. Here, we review approaches to germline genetic testing, highlighting key points in a typical patient's course that present challenges for testing and interpreting results. Increasing awareness by health care providers of these conditions and improvements in testing platforms are crucial for enabling a proactive approach to tailoring a suitable treatment plan and surveillance program for the patient and their family members.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141522745","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 : 2024-06-18DOI: 10.1146/annurev-cancerbio-061421-041946
Xiaoyu Zhang, Benjamin F. Cravatt
Advances in genome sequencing and editing technologies have enriched our understanding of the biochemical pathways that drive tumorigenesis. Translating this knowledge into new medicines for cancer treatment, however, remains challenging, and many oncogenic proteins have proven recalcitrant to conventional approaches for chemical probe and drug discovery. Here, we discuss how innovations in chemical proteomics and covalent chemistry are being integrated to identify and advance first-in-class small molecules that target cancer-relevant proteins. Mechanistic studies have revealed that covalent compounds perturb protein functions in cancer cells in diverse ways that include the remodeling of protein–protein and protein–RNA complexes, as well as through alterations in posttranslational modification. We speculate on the attributes of chemical proteomics and covalent chemistry that have enabled targeting of previously inaccessible cancer-relevant pathways and consider technical challenges that remain to be addressed in order to fully realize the druggability of the cancer proteome.
{"title":"Chemical Proteomics–Guided Discovery of Covalent Ligands for Cancer Proteins","authors":"Xiaoyu Zhang, Benjamin F. Cravatt","doi":"10.1146/annurev-cancerbio-061421-041946","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061421-041946","url":null,"abstract":"Advances in genome sequencing and editing technologies have enriched our understanding of the biochemical pathways that drive tumorigenesis. Translating this knowledge into new medicines for cancer treatment, however, remains challenging, and many oncogenic proteins have proven recalcitrant to conventional approaches for chemical probe and drug discovery. Here, we discuss how innovations in chemical proteomics and covalent chemistry are being integrated to identify and advance first-in-class small molecules that target cancer-relevant proteins. Mechanistic studies have revealed that covalent compounds perturb protein functions in cancer cells in diverse ways that include the remodeling of protein–protein and protein–RNA complexes, as well as through alterations in posttranslational modification. We speculate on the attributes of chemical proteomics and covalent chemistry that have enabled targeting of previously inaccessible cancer-relevant pathways and consider technical challenges that remain to be addressed in order to fully realize the druggability of the cancer proteome.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141522747","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 : 2024-06-18DOI: 10.1146/annurev-cancerbio-062822-105541
Thea D. Tlsty
Cancer research seeks to understand the biology underlying the progression to malignant transformation. Recently, the incidence of esophageal adenocarcinoma (EAC) has increased dramatically, and if we understand why and how, we will be better equipped for diagnosis, prognosis, detection, prevention, and intervention. The earliest steps in progression for most malignancies are the most difficult to study. The initiation of cancer is believed to be a relatively rare and sporadic event, the locations and timings of which are most often unknown. Of the trillions of somatic cells in our bodies, only a few ever find themselves on a path to malignancy. However, chronic inflammation generates a metaplastic lesion that is directly linked to increased incidence of EAC and thus alerts us to the time and place that progression is initiated and allows us to study the biology. We describe recent studies that identify coordinated actions between stromal and epithelial cells that progress to EAC.
{"title":"Studying Progression from Chronic Injury to Esophageal Adenocarcinoma","authors":"Thea D. Tlsty","doi":"10.1146/annurev-cancerbio-062822-105541","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-105541","url":null,"abstract":"Cancer research seeks to understand the biology underlying the progression to malignant transformation. Recently, the incidence of esophageal adenocarcinoma (EAC) has increased dramatically, and if we understand why and how, we will be better equipped for diagnosis, prognosis, detection, prevention, and intervention. The earliest steps in progression for most malignancies are the most difficult to study. The initiation of cancer is believed to be a relatively rare and sporadic event, the locations and timings of which are most often unknown. Of the trillions of somatic cells in our bodies, only a few ever find themselves on a path to malignancy. However, chronic inflammation generates a metaplastic lesion that is directly linked to increased incidence of EAC and thus alerts us to the time and place that progression is initiated and allows us to study the biology. We describe recent studies that identify coordinated actions between stromal and epithelial cells that progress to EAC.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141522748","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 : 2024-06-18DOI: 10.1146/annurev-cancerbio-062722-021823
Iva Simeonova, Geneviève Almouzni
Our understanding of cancer genomes has allowed for the integration of molecular data into histopathological classifications for routine stratification of patients. In the last 10–15 years, thanks to this systematic implementation of large-scale sequencing, the identification of hotspot somatic mutations in histone genes came into the limelight, underscoring the concept of oncohistones. As drivers in pediatric brain tumors, and in several other types of cancers, oncohistones brought a “new dimension of Strange” into the cancer multiverse, to paraphrase Marvel. An integrative approach to cancer complexity as a multidimensional projection is urgently needed to consider all relevant etiological, developmental, and evolutionary components. Here, we discuss recent progress on histone variants and chaperones, their regulation and alterations in cancers, the available in vivo models, and current treatment strategies. More specifically, we adopt a view through the lens of tissue-specific differences and means for genome expression and integrity maintenance.
{"title":"Histone H3 Variants in the Multiverse of Cancer","authors":"Iva Simeonova, Geneviève Almouzni","doi":"10.1146/annurev-cancerbio-062722-021823","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062722-021823","url":null,"abstract":"Our understanding of cancer genomes has allowed for the integration of molecular data into histopathological classifications for routine stratification of patients. In the last 10–15 years, thanks to this systematic implementation of large-scale sequencing, the identification of hotspot somatic mutations in histone genes came into the limelight, underscoring the concept of oncohistones. As drivers in pediatric brain tumors, and in several other types of cancers, oncohistones brought a “new dimension of Strange” into the cancer multiverse, to paraphrase Marvel. An integrative approach to cancer complexity as a multidimensional projection is urgently needed to consider all relevant etiological, developmental, and evolutionary components. Here, we discuss recent progress on histone variants and chaperones, their regulation and alterations in cancers, the available in vivo models, and current treatment strategies. More specifically, we adopt a view through the lens of tissue-specific differences and means for genome expression and integrity maintenance.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141503704","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 : 2024-06-18DOI: 10.1146/annurev-cancerbio-062822-102816
Robert A. Weinberg
Through a series of accidents of history, my career began just when the revolution in molecular biology was taking place. The allure of molecular biology attracted me to exploiting tumor viruses as experimental models of the nucleic acid metabolism of cells. The fact that these viruses cause cancer was incidental but eventually led to an interest in cancer pathogenesis, exploiting them to understand the mechanisms of cell transformation. This made it possible to test the speculation that cell transformation derived from the mutation of cellular genes and that cancer cell behavior is driven by the actions of resulting mutant alleles of these genes. In 1979, we showed that cells that had been transformed by 3-methylcholanthrene carried a mutant oncogenic allele. This work progressed so that by 1982 my research group and others demonstrated that human bladder carcinoma cells carried a point-mutated RAS oncogene, providing a direct proof of the mutational theory of cancer pathogenesis.
{"title":"An Erratic Path Toward Discovery","authors":"Robert A. Weinberg","doi":"10.1146/annurev-cancerbio-062822-102816","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-102816","url":null,"abstract":"Through a series of accidents of history, my career began just when the revolution in molecular biology was taking place. The allure of molecular biology attracted me to exploiting tumor viruses as experimental models of the nucleic acid metabolism of cells. The fact that these viruses cause cancer was incidental but eventually led to an interest in cancer pathogenesis, exploiting them to understand the mechanisms of cell transformation. This made it possible to test the speculation that cell transformation derived from the mutation of cellular genes and that cancer cell behavior is driven by the actions of resulting mutant alleles of these genes. In 1979, we showed that cells that had been transformed by 3-methylcholanthrene carried a mutant oncogenic allele. This work progressed so that by 1982 my research group and others demonstrated that human bladder carcinoma cells carried a point-mutated <jats:italic>RAS</jats:italic> oncogene, providing a direct proof of the mutational theory of cancer pathogenesis.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141503705","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 : 2024-06-18DOI: 10.1146/annurev-cancerbio-061223-094639
Jordan H. Driskill, Josephine K. Dermawan, Cristina R. Antonescu, Duojia Pan
Gene fusions are well-known drivers of cancer and are potent targets for molecular therapy. An emerging spectrum of human tumors harbors recurrent and pathognomonic gene fusions that involve the transcriptional coactivator YAP1 (which encodes the protein YAP) or its paralog WWTR1 (which encodes the protein TAZ). YAP and TAZ are frequently activated in cancer and are the transcriptional effectors of the Hippo pathway, a highly conserved kinase cascade that regulates diverse functions such as organ size, development, and homeostasis. In this review, we discuss the tumors that have YAP, TAZ, or other Hippo-dysregulating fusion proteins; the mechanisms of these fusion proteins in driving their respective tumors; and the potential vulnerabilities of these chimeric oncoproteins across cancers of many origins. Furthermore, as new YAP1 and WWTR1 gene fusions are discovered, we provide a framework to predict whether the resulting protein product is likely to be oncogenic.
{"title":"YAP, TAZ, and Hippo-Dysregulating Fusion Proteins in Cancer","authors":"Jordan H. Driskill, Josephine K. Dermawan, Cristina R. Antonescu, Duojia Pan","doi":"10.1146/annurev-cancerbio-061223-094639","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061223-094639","url":null,"abstract":"Gene fusions are well-known drivers of cancer and are potent targets for molecular therapy. An emerging spectrum of human tumors harbors recurrent and pathognomonic gene fusions that involve the transcriptional coactivator <jats:italic>YAP1</jats:italic> (which encodes the protein YAP) or its paralog <jats:italic>WWTR1</jats:italic> (which encodes the protein TAZ). YAP and TAZ are frequently activated in cancer and are the transcriptional effectors of the Hippo pathway, a highly conserved kinase cascade that regulates diverse functions such as organ size, development, and homeostasis. In this review, we discuss the tumors that have YAP, TAZ, or other Hippo-dysregulating fusion proteins; the mechanisms of these fusion proteins in driving their respective tumors; and the potential vulnerabilities of these chimeric oncoproteins across cancers of many origins. Furthermore, as new <jats:italic>YAP1</jats:italic> and <jats:italic>WWTR1</jats:italic> gene fusions are discovered, we provide a framework to predict whether the resulting protein product is likely to be oncogenic.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141522746","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 : 2024-06-18DOI: 10.1146/annurev-cancerbio-062822-122840
Anke Vandekeere, Sarah El Kharraz, Patricia Altea-Manzano, Sarah-Maria Fendt
Following escape from the primary tumor, cancer cells face diverse micro-environments during the metastatic cascade. To survive and establish outgrowth at a distant site, metastasizing cancer cells must undergo metabolic reprogramming to adapt to the changing conditions. However, the host in which the tumors grow also experiences metabolic adaptations in response to various environmental factors that can mediate cancer progression. In this review, we highlight the endogenous factors that determine host metabolism (nutrient availability at specific organs or the microbiome), as well as exogenous factors that influence host metabolism systemically or locally (diet, alcohol, physical activity, air pollution, and circadian rhythm). Furthermore, we elaborate on how these environment-induced metabolic changes can affect metastatic progression. Understanding the interplay between environmental factors, host metabolism, and metastatic progression may unveil potential targets for future therapeutic interventions.
{"title":"Metabolic Rewiring During Metastasis: The Interplay Between the Environment and the Host","authors":"Anke Vandekeere, Sarah El Kharraz, Patricia Altea-Manzano, Sarah-Maria Fendt","doi":"10.1146/annurev-cancerbio-062822-122840","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-122840","url":null,"abstract":"Following escape from the primary tumor, cancer cells face diverse micro-environments during the metastatic cascade. To survive and establish outgrowth at a distant site, metastasizing cancer cells must undergo metabolic reprogramming to adapt to the changing conditions. However, the host in which the tumors grow also experiences metabolic adaptations in response to various environmental factors that can mediate cancer progression. In this review, we highlight the endogenous factors that determine host metabolism (nutrient availability at specific organs or the microbiome), as well as exogenous factors that influence host metabolism systemically or locally (diet, alcohol, physical activity, air pollution, and circadian rhythm). Furthermore, we elaborate on how these environment-induced metabolic changes can affect metastatic progression. Understanding the interplay between environmental factors, host metabolism, and metastatic progression may unveil potential targets for future therapeutic interventions.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141503702","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 : 2024-06-18DOI: 10.1146/annurev-cancerbio-062822-025055
Matthew F. Jones, Catherine C. Smith
The treatment of acute myeloid leukemia (AML) has historically relied on cytotoxic chemotherapy, but modern understanding of AML biology has paved the way for new treatments that target the molecular pathways that drive AML, in particular FLT3, IDH1/IDH2, and BCL2. Many of these targeted therapies are effective, but responses are typically short-lived and resistance remains a ubiquitous clinical problem. Understanding the mechanisms of resistance to targeted therapy is essential to continue improving AML therapy. Recent studies have shed new light on the ways in which AML evades targeted inhibition, including on-target resistance mutations, mutations in parallel molecular pathways, and plasticity in cellular state. In this review, we outline the mechanisms of resistance to commonly used targeted therapies in AML and discuss ideas to overcome the urgent problem of resistance.
急性髓性白血病（AML）的治疗历来依赖于细胞毒性化疗，但对 AML 生物学的现代认识为针对驱动 AML 的分子通路（尤其是 FLT3、IDH1/IDH2 和 BCL2）的新疗法铺平了道路。其中许多靶向疗法是有效的，但反应通常是短暂的，耐药性仍然是一个普遍存在的临床问题。了解靶向治疗的耐药机制对于继续改善急性髓细胞性白血病的治疗至关重要。最近的研究揭示了急性髓细胞性白血病逃避靶向抑制的新途径，包括靶向耐药突变、平行分子通路的突变以及细胞状态的可塑性。在这篇综述中，我们概述了急性髓细胞性白血病常用靶向疗法的耐药机制，并探讨了克服耐药这一紧迫问题的思路。
{"title":"Mechanisms of Resistance to Targeted Therapies in AML","authors":"Matthew F. Jones, Catherine C. Smith","doi":"10.1146/annurev-cancerbio-062822-025055","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-025055","url":null,"abstract":"The treatment of acute myeloid leukemia (AML) has historically relied on cytotoxic chemotherapy, but modern understanding of AML biology has paved the way for new treatments that target the molecular pathways that drive AML, in particular FLT3, IDH1/IDH2, and BCL2. Many of these targeted therapies are effective, but responses are typically short-lived and resistance remains a ubiquitous clinical problem. Understanding the mechanisms of resistance to targeted therapy is essential to continue improving AML therapy. Recent studies have shed new light on the ways in which AML evades targeted inhibition, including on-target resistance mutations, mutations in parallel molecular pathways, and plasticity in cellular state. In this review, we outline the mechanisms of resistance to commonly used targeted therapies in AML and discuss ideas to overcome the urgent problem of resistance.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141503703","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 : 2024-01-25DOI: 10.1146/annurev-cancerbio-062722-035210
Pamela S. Herrera, Marcel van den Brink
The intestinal microbiota, a complex ecosystem of microorganisms, has emerged as an important player in modulating various aspects of human health and disease. The microbiota is in a state of constant cross talk with itself and its host, and these interactions regulate several aspects of host homeostasis, including immune responses. Studies have demonstrated a relationship between the microbiota and outcomes of several cancer immunotherapies. This review explores the different roles of the microbiota in shaping the efficacy and safety of cancer immunotherapies, including allogeneic hematopoietic cell transplantation, immune checkpoint blockade, and CAR T cell therapy.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":"The Intestinal Microbiota and Therapeutic Responses to Immunotherapy","authors":"Pamela S. Herrera, Marcel van den Brink","doi":"10.1146/annurev-cancerbio-062722-035210","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062722-035210","url":null,"abstract":"The intestinal microbiota, a complex ecosystem of microorganisms, has emerged as an important player in modulating various aspects of human health and disease. The microbiota is in a state of constant cross talk with itself and its host, and these interactions regulate several aspects of host homeostasis, including immune responses. Studies have demonstrated a relationship between the microbiota and outcomes of several cancer immunotherapies. This review explores the different roles of the microbiota in shaping the efficacy and safety of cancer immunotherapies, including allogeneic hematopoietic cell transplantation, immune checkpoint blockade, and CAR T cell therapy.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":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139589632","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 : 2024-01-12DOI: 10.1146/annurev-cancerbio-062822-110356
Dominic D.G. Owens, Matthew E.R. Maitland, Cheryl H. Arrowsmith, Dalia Barsyte-Lovejoy
In this review, we explore the current landscape of preclinical and clinical therapeutics targeting epigenetic complexes in cancer, focusing on targets with enzymatic inhibitors, degraders, or ligands capable of disrupting protein–protein interactions. Current strategies face challenges such as limited single-agent clinical efficacy due to insufficient disruption of chromatin complexes and incomplete dissociation from chromatin. Further complications arise from the adaptability of cancer cell chromatin and, in some cases, dose-limiting toxicity. The advent of targeted protein degradation (TPD) through degrader compounds such as proteolysis-targeting chimeras provides a promising approach. These innovative molecules exploit the endogenous ubiquitin–proteasome system to catalytically degrade target proteins and disrupt complexes, potentially amplifying the efficacy of existing epigenetic binders. We highlight the status of TPD-harnessing moieties in clinical and preclinical development, as these compounds may prove crucial for unlocking the potential of epigenetic complex modulation in cancer therapeutics.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 Discovery for Chromatin Complexes: Where Do We Stand?","authors":"Dominic D.G. Owens, Matthew E.R. Maitland, Cheryl H. Arrowsmith, Dalia Barsyte-Lovejoy","doi":"10.1146/annurev-cancerbio-062822-110356","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-110356","url":null,"abstract":"In this review, we explore the current landscape of preclinical and clinical therapeutics targeting epigenetic complexes in cancer, focusing on targets with enzymatic inhibitors, degraders, or ligands capable of disrupting protein–protein interactions. Current strategies face challenges such as limited single-agent clinical efficacy due to insufficient disruption of chromatin complexes and incomplete dissociation from chromatin. Further complications arise from the adaptability of cancer cell chromatin and, in some cases, dose-limiting toxicity. The advent of targeted protein degradation (TPD) through degrader compounds such as proteolysis-targeting chimeras provides a promising approach. These innovative molecules exploit the endogenous ubiquitin–proteasome system to catalytically degrade target proteins and disrupt complexes, potentially amplifying the efficacy of existing epigenetic binders. We highlight the status of TPD-harnessing moieties in clinical and preclinical development, as these compounds may prove crucial for unlocking the potential of epigenetic complex modulation in cancer therapeutics.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":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139462039","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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